Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof

ABSTRACT

Described herein are compounds that are LOXL2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with LOXL2 activity.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/293,248, filed on Feb. 9, 2016, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds that are lysyl oxidase-like 2 (LOXL2)inhibitors, methods of making such compounds, pharmaceuticalcompositions, and medicaments comprising such compounds, and methods ofusing such compounds in the treatment of conditions, diseases, ordisorders associated with LOXL2 activity.

BACKGROUND OF THE INVENTION

Lysyl oxidase like-2 (LOXL2) is an amine oxidase enzyme that catalyzescrosslinking of extracellular matrix proteins. LOXL2 is also involved inintracellular processes such as mediating epithelial-to-mesenchymaltransition of cells. LOXL2 signaling is implicated in, for example,fibrotic diseases and cancer.

SUMMARY OF THE INVENTION

In one aspect, described herein are LOXL2 inhibitors and uses thereof.In some embodiments, the LOXL2 inhibitors described herein have thestructure of Formula (I), or a pharmaceutically acceptable salt, orsolvate thereof.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R² is Br, —CN, —OH, —OC₂-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,        —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, —OC₁-C₆deuteroalkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆alkynyl;    -   or R² is A-L¹-;        -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,            C₁-C₆alkylene, —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-,            —S(C₁-C₆alkylene)-, —S═O(C₁-C₆alkylene)-, or            —S(═O)₂C₁-C₆alkylene-;        -   A is a cyclic ring that is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkenyl, or substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, wherein if A is            substituted then A is substituted with one or more R⁶;            -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,                —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,                —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,                substituted or unsubstituted C₁-C₆alkyl, substituted or                unsubstituted C₁-C₆fluoroalkyl, substituted or                unsubstituted C₁-C₆deuteroalkyl, substituted or                unsubstituted C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₃-C₁₀deuterocycloalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀deuterocycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₃-C₁₀deuterocycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, —OC₁-C₆deuteroalkyl, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments,each R¹ is independently H, D, or F. In other embodiments, each R¹ isindependently H, or D. In some other embodiments, each R¹ is H.

In some embodiments, the compound has the structure of Formula (II):

In some embodiments, the compound has the structure of Formula (III):

In some embodiments, the compound has the structure of Formula (IV):

In some embodiments, the compound has the structure of Formula (V), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl;

-   -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,        —NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4.

In some embodiments, the compound has the structure of Formula (VI):

In some embodiments, the compound has the structure of Formula (VII):

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In one aspect, described herein is a pharmaceutical compositioncomprising a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, and at least one pharmaceutically acceptableexcipient. In some embodiments, the pharmaceutical composition isformulated for administration to a mammal by intravenous administration,subcutaneous administration, oral administration, inhalation, nasaladministration, dermal administration, or ophthalmic administration. Insome embodiments, the pharmaceutical composition is formulated foradministration to a mammal by intravenous administration, subcutaneousadministration, or oral administration. In some embodiments, thepharmaceutical composition is formulated for administration to a mammalby oral administration. In some embodiments, the pharmaceuticalcomposition is in the form of a tablet, a pill, a capsule, a liquid, asuspension, a gel, a dispersion, a solution, an emulsion, an ointment,or a lotion. In some embodiments, the pharmaceutical composition is inthe form of a tablet, a pill, or a capsule.

In one aspect, described herein is a method of treating a disease orcondition in a mammal that would benefit from the inhibition orreduction of Lysyl oxidase like-2 (LOXL2) activity comprisingadministering a substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, to the mammal in need thereof.

In some embodiments, the disease or condition is fibrosis or cancer. Insome embodiments, the disease or condition is fibrosis. In someembodiments, the fibrosis comprises lung fibrosis, liver fibrosis,kidney fibrosis, cardiac fibrosis, peritoneal fibrosis, ocular fibrosisor cutaneous fibrosis. In some embodiments, the fibrosis ismyelofibrosis.

In some embodiments, the substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, is a Lysyl oxidase like-2 (LOXL2)inhibitor.

In some embodiments, the substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, has the structure of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R² is H, D, F, Cl, Br, I, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂,        —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,        —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        —OC₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₆alkenyl, or        substituted or unsubstituted C₂-C₆alkynyl;    -   or R² is A-L¹-;        -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,            C₁-C₆alkylene, —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-,            —S(C₁-C₆alkylene)-, —S═O(C₁-C₆alkylene)-, or            —S(═O)₂C₁-C₆alkylene-;        -   A is a cyclic ring that is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkenyl, or substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, wherein if R² is            substituted then R² is substituted with one or more R⁶;            -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,                —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,                —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,                substituted or unsubstituted C₁-C₆alkyl, substituted or                unsubstituted C₁-C₆fluoroalkyl, substituted or                unsubstituted C₁-C₆deuteroalkyl, substituted or                unsubstituted C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₃-C₁₀cyclodeuteroalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, —OC₁-C₆deuteroalkyl, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2.

In some embodiments, the compound has the structure of Formula (II):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (III):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (IV):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (V), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl;

-   -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,        —NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4.

In some embodiments, the compound has the structure of Formula (VI):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (VII):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound is administered to the mammal byintravenous administration, subcutaneous administration, oraladministration, inhalation, nasal administration, dermal administration,or ophthalmic administration.

In one aspect, described herein is a method of treating or preventingany one of the diseases or conditions described herein comprisingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof, to amammal in need thereof.

In one aspect, described herein is a method for the treatment orprevention of fibrosis in a mammal comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof.

In other embodiments, the fibrosis is amenable to treatment with a LOXL2inhibitor. In some embodiments, the fibrosis is lung fibrosis. In someembodiments, the method further comprises administering a secondtherapeutic agent to the mammal in addition to the compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt, or solvate thereof, is: (a)systemically administered to the mammal; and/or (b) administered orallyto the mammal; and/or (c) intravenously administered to the mammal;and/or (d) administered by inhalation; and/or (e) administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) adminstered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the aforementioned aspects involving the treatment of adisease or condition are further embodiments comprising administering atleast one additional agent in addition to the administration of acompound of Formula (I) described herein, or a pharmaceuticallyacceptable salt, or solvate thereof. In various embodiments, each agentis administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

Articles of manufacture, which include packaging material, a compounddescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, within the packaging material, and a label that indicates thatthe compound or composition, or pharmaceutically acceptable salt,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, is used for inhibitingthe activity of LOXL2, or for the treatment, prevention or ameliorationof one or more symptoms of a disease or condition that would benefitfrom inhibition or reduction of the LOXL2 activity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Lysyl oxidase like-2 (LOXL2) is a member of the lysyl oxidase (LOX)family, which comprises Cu²⁺ and lysine tyrosylquinone (LTQ)-dependentamine oxidases. The family comprises five genes: lox (LOX), loxl1 (lysyloxidase like-1, LOXL1), loxl2 (LOXL2), loxl3 (lysyl oxidase like-3,LOXL3), and loxl4 (lysyl oxidase like-4, LOXL4). The LOX family is knownfor catalyzing the oxidative deamination of the ε-amino group of lysinesand hydroxylysines in collagen and elastin to promote crosslinking ofthese molecules. Crosslinking of collagen and elastin is essential formaintaining tensile strength of the extracellular matrix.

LOXL2 has been demonstrated to have intracellular functions aside fromits role in remodeling of the extracellular matrix. LOXL2 positivelyregulates the epithelial-to-mesenchymal transition (EMT) transducer,Snail1, by promoting Snail1 stability and functional activity. LOXL2contributes positively to the activation of the focal adhesion kinase(FAK) signaling pathway and participates in the organization of focaladhesion complexes. Silencing of LOXL2 gene leads to reacquisition ofepithelial cell polarity and decreases the migratory and invasiveability of mammary cell lines. The modulation of cell adhesion and cellpolarity has been reported to be mediated by intracellular LOXL2. LOXL2transcriptionally represses E-cadherin as well as tight junction andcell polarity genes by Snail1-dependent and Snail1-independentmechanisms. LOXL2 has been more recently described to be associated withchromatin and reported to be involved in histone H2 deamination, afunction that is dependent on the LOXL2 catalytic domain.

In some embodiments, the methods disclosed herein are methods forinhibiting intracellular LOXL2. In some embodiments, the methodsdisclosed herein are methods for inhibiting extracellular (secreted)LOXL2. In some embodiments, the methods disclosed herein are methods forinhibiting extracellular and intracellular LOXL2.

Fibrosis

LOXL2 has been shown to be involved in fibrotic processes. Fibroticprocesses include an excessive deposition of extracellular matrixcomponents, such as collagen, which alters the physical, biochemical,and biomechanical matrix properties leading to defective organ functionand organ failure. Tissue fibrosis is also associated with cancerprogression by direct promotion of cellular transformation andmetastasis. Tumors are typically stiffer than normal tissue and tumorrigidity influences tumor metastasis.

Excessive LOXL2 enzyme activity has been implicated in the increasedstiffness of tumors. Elevated LOXL2 is also associated with fibroticlesions from livers of patients suffering from Wilson disease andprimary biliary cirrhosis. Additionally, the administration of aLOXL2-specific monoclonal antibody AB0023 was efficacious in reducingdisease in a model of fibrosis. AB0023 was shown to inhibit theproduction of growth factors and of crosslinked collagenous matrix andTGF-beta signaling.

In some embodiments, disclosed herein are methods of treating fibrosiswith a compound disclosed herein.

“Fibrosis,” as used herein, refers to the accumulation of extracellularmatrix constituents that occurs following trauma, inflammation, tissuerepair, immunological reactions, cellular hyperplasia, and neoplasia.

In some embodiments, disclosed herein is a method of reducing fibrosisin a tissue comprising contacting a fibrotic cell or tissue with acompound disclosed herein, in an amount sufficient to decrease orinhibit the fibrosis. In some embodiments, the fibrosis includes afibrotic condition.

In some embodiments, the fibrosis comprises lung fibrosis, liverfibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis, ocularfibrosis or cutaneous fibrosis. In some embodiments, the fibrosiscomprises lung fibrosis. In some embodiments, the fibrosis comprisesliver fibrosis. In some embodiments, the fibrosis comprises kidneyfibrosis. In some embodiments, the fibrosis comprises cardiac fibrosis.In some embodiments, the fibrosis comprises peritoneal fibrosis. In someembodiments, the fibrosis comprises ocular fibrosis. In someembodiments, the fibrosis comprises cutaneous fibrosis.

In some embodiments, reducing fibrosis, or treatment of a fibroticcondition, includes reducing or inhibiting one or more of: formation ordeposition of extracellular matrix proteins; the number of pro-fibroticcell types (e.g., fibroblast or immune cell numbers); cellular collagenor hydroxyproline content within a fibrotic lesion; expression oractivity of a fibrogenic protein; or reducing fibrosis associated withan inflammatory response.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe lung.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe liver.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe heart.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe kidney.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe skin.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe eye.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe gastrointestinal tract.

In some embodiments, the fibrotic condition is a fibrotic condition ofthe bone marrow.

In some embodiments, the fibrotic condition is idiopathic. In someembodiments, the fibrotic condition is associated with (e.g., issecondary to) a disease (e.g., an infectious disease, an inflammatorydisease, an autoimmune disease, a malignant or cancerous disease, and/ora connective disease); a toxin; an insult (e.g., an environmental hazard(e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarettesmoking, a wound); a medical treatment (e.g., surgical incision,chemotherapy or radiation), or a combination thereof.

In some embodiments, disclosed herein is a method for the treatment orprevention of fibrosis in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable salt, orsolvate thereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method of improving lungfunction in a mammal comprising administering a LOXL2 inhibitordescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, to the mammal in need thereof. In some embodiments, the mammalhas been diagnosed as having lung fibrosis.

In some embodiments, disclosed herein is a method of treating idopathicpulmonary fibrosis in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable salt, orsolvate thereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method of controlling anabnormal accumulation or activation of cells, fibronectin, collagen orincreased fibroblast recruitment in a tissue of a mammal comprisingadministering a LOXL2 inhibitor described herein, or a pharmaceuticallyacceptable salt, or solvate thereof, to the mammal in need thereof. Insome embodiments, the abnormal accumulation or activation of cells,fibronectin, collagen or increased fibroblast recruitment in the tissueresults in fibrosis.

In some embodiments, disclosed herein is a method for the treatment orprevention of scleroderma in a mammal comprising administering a LOXL2inhibitor described herein, or a pharmaceutically acceptable salt, orsolvate thereof, to the mammal in need thereof.

In some embodiments, disclosed herein is a method for reducing undesiredor abnormal dermal thickening in a mammal comprising administering tomammal in need thereof a LOXL2 inhibitor described herein, or apharmaceutically acceptable salt, or solvate thereof. In someembodiments, the dermal thickening is associated with scleroderma.

In some embodiments, described herein is a method of controlling anabnormal accumulation or activation of cells, fibronectin, collagen orincreased fibroblast recruitment in tissues of a mammal comprisingadministering to mammal in need thereof a LOXL2 inhibitor describedherein, or a pharmaceutically acceptable salt, or solvate thereof. Insome embodiments, the abnormal accumulation or activation of cells,fibronectin, collagen or increased fibroblast recruitment in the dermaltissues results in fibrosis. In some embodiments, described herein is amethod of reducing hydroxyproline content in tissues of a mammal withfibrosis comprising administering to mammal in need thereof a LOXL2inhibitor described herein, or a pharmaceutically acceptable salt, orsolvate thereof.

Cancer

LOXL2 has been shown to be involved in signaling related to cancer cellgrowth, adhesion, motility and invasion. Specifically, LOXL2 inducesepithelial-to-mesenchymal transition (EMT) of cells to promote tumorinvasion. LOXL2 is also upregulated in hypoxic tumor environments whichleads to enhanced invasion of tumor cells. LOXL2 has also been shown topromote angiogenesis in hypoxic tumor environments.

Increased LOXL2 expression is associated with poor prognosis in patientswith colon, esophageal tumors, oral squamous cell carcinomas, laryngealsquamous cell carcinomas, and head and neck squamous cell carcinomas.LOXL2 has been proposed to participate in cancers of the breast, colon,gastric, head and neck, lung, and melanoma.

In some embodiments, disclosed herein are methods of treating cancerwith a compound disclosed herein.

The term “cancer” as used herein, refers to an abnormal growth of cellsthat tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). Types of cancer include, but are not limited to,solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue(lymphoma), ovary, pancreas or other endocrine organ (thyroid),prostate, skin (melanoma or basal cell cancer) or hematological tumors(such as the leukemias and lymphomas) at any stage of the disease withor without metastases.

In one aspect, described herein is a method of treating a disease orcondition in a mammal that would benefit from the inhibition orreduction of Lysyl oxidase like-2 (LOXL2) activity comprisingadministering a substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, to the mammal in need thereof. Insome embodiments, the substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, is a Lysyl oxidase like-2 (LOXL2)inhibitor. In some embodiments, the substituted or unsubstituted2-(aminomethyl)quinolin-4(1H)-one compound, or pharmaceuticallyacceptable salt, or solvate thereof, has the structure of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F; R² is H, D, F, Cl, Br, I,        —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴,        —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴,        —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂,        —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        substituted or unsubstituted C₁-C₆deuteroalkyl, substituted or        unsubstituted —OC₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₆alkenyl, or        substituted or unsubstituted C₂-C₆alkynyl;    -   or R² is A-L¹-;        -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,            C₁-C₆alkylene, —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-,            —S(C₁-C₆alkylene)-, —S═O(C₁-C₆alkylene)-, or            —S(═O)₂C₁-C₆alkylene-;        -   A is a cyclic ring that is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkenyl, or substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, wherein if R² is            substituted then R² is substituted with one or more R⁶;            -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,                —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,                —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,                substituted or unsubstituted C₁-C₆alkyl, substituted or                unsubstituted C₁-C₆fluoroalkyl, substituted or                unsubstituted C₁-C₆deuteroalkyl, substituted or                unsubstituted C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₃-C₁₀cyclodeuteroalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, —OC₁-C₆deuteroalkyl, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments,each R¹ is independently H, D, or F. In other embodiments, each R¹ isindependently H, or D. In some other embodiments, each R¹ is H.

In some embodiments, the compound has the structure of Formula (II):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (III):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (IV):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is H, D, Br, —CN, —OH, —OC₁-C₆alkyl,—OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂,—NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,—OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,substituted or unsubstituted C₁-C₆deuteroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆alkynyl. In someembodiments, R² is H, F, Cl, Br, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl, or substituted orunsubstituted C₂-C₆alkynyl. In some embodiments, R² is Br.

In some embodiments, R² is A-L¹-; L¹ is absent; A is a cyclic ring thatis a substituted or unsubstituted phenyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₃-C₈cycloalkenyl, or substituted orunsubstituted C₂-C₈heterocycloalkyl, wherein if A is substituted then Ais substituted with one or more R⁶.

In some embodiments, A is a substituted or unsubstituted phenyl, whereinif A is substituted then A is substituted with one or more R⁶.

In some embodiments, A is a substituted or unsubstituted monocyclicheteroaryl, wherein if A is substituted then A is substituted with oneor more R⁶.

In some embodiments, A is a substituted or unsubstituted monocyclic5-membered heteroaryl or a substituted or unsubstituted monocyclic6-membered heteroaryl, wherein if A is substituted then A is substitutedwith one or more R⁶.

In some embodiments, A is substituted or unsubstituted monocyclicheteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, orsubstituted or unsubstituted monocyclic heteroaryl containing 0-4 Natoms and 1 O or S atoms, wherein if A is substituted then A issubstituted with one or more R⁶.

In some embodiments, A is substituted or unsubstituted monocyclicheteroaryl that is a substituted or unsubstituted furanyl, substitutedor unsubstituted thienyl, substituted or unsubstituted pyrrolyl,substituted or unsubstituted oxazolyl, substituted or unsubstitutedthiazolyl, substituted or unsubstituted imidazolyl, substituted orunsubstituted pyrazolyl, substituted or unsubstituted triazolyl,substituted or unsubstituted tetrazolyl, substituted or unsubstitutedisoxazolyl, substituted or unsubstituted isothiazolyl, substituted orunsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl,substituted or unsubstituted pyridinyl, substituted or unsubstitutedpyrimidinyl, substituted or unsubstituted pyrazinyl, substituted orunsubstituted pyridazinyl, or a substituted or unsubstituted triazinyl,wherein if A is substituted then A is substituted with one or more R⁶.

In some embodiments, A is substituted or unsubstituted C₃-C₆cycloalkyl,wherein if A is substituted then A is substituted with one or more R⁶.In some embodiments, A is substituted or unsubstituted C₃-C₆cycloalkylthat is a substituted or unsubstituted cyclopropyl, substituted orunsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, orsubstituted or unsubstituted cyclohexyl, wherein if A is substitutedthen A is substituted with one or more R⁶.

In some embodiments, A is substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, wherein if A is substituted then R² issubstituted with one or more R⁶. In some embodiments, A is substitutedor unsubstituted C₂-C₁₀heterocycloalkyl that is substituted orunsubstituted pyrrolidinonyl, substituted or unsubstitutedoxazolidinonyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,substituted or unsubstituted piperazinyl, substituted or unsubstitutedaziridinyl, substituted or unsubstituted azetidinyl, substituted orunsubstituted oxetanyl, substituted or unsubstituted thietanyl,substituted or unsubstituted homopiperidinyl, substituted orunsubstituted oxepanyl, substituted or unsubstituted thiepanyl,substituted or unsubstituted oxazepinyl, substituted or unsubstituteddiazepinyl, substituted or unsubstituted thiazepinyl, or substituted orunsubstituted 1,2,3,6-tetrahydropyridinyl, wherein if A is substitutedthen A is substituted with one or more R⁶.

In some embodiments, the compound has the structure of Formula (Va), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂₋, C₁-C₆alkylene,        —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,        —S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-;    -   ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl;

-   -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,        —NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4.

In some embodiments, the compound has the structure of Formula (Vb), ora pharmaceutically acceptable salt, or solvate thereof:

In some embodiments, ring

is phenyl. In some embodiments,

In some embodiments, ring

is a monocyclic 6-membered heteroaryl. In some embodiments,

In some embodiments, ring

is a monocyclic 5-membered heteroaryl. In some embodiments,

In some embodiments,

In some embodiments, ring

is C₃-C₆cycloalkyl. In some embodiments, ring

is C₃-C₆cycloalkyl that is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

In some embodiments, ring

is C₂-C₁₀heterocycloalkyl. In some embodiments, ring

is C₂-C₁₀heterocycloalkyl that is pyrrolidinonyl, oxazolidinonyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, or 1,2,3,6-tetrahydropyridinyl.

In some embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted monocyclicC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, the compound has the structure of Formula (VI):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (VII):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

Compounds described herein, including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are LOXL2 inhibitors.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   each R¹ is independently H, D, or F;    -   R² is Br, —CN, —OH, —OC₂-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,        —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, —OC₁-C₆deuteroalkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆alkynyl;    -   or R² is A-L¹-;        -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,            C₁-C₆alkylene, —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-,            —S(C₁-C₆alkylene)-, —S═O(C₁-C₆alkylene)-, or            —S(═O)₂C₁-C₆alkylene-;        -   A is a cyclic ring that is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkenyl, or substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, wherein if A is            substituted then A is substituted with one or more R⁶;            -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,                —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,                —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,                —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,                substituted or unsubstituted C₁-C₆alkyl, substituted or                unsubstituted C₁-C₆fluoroalkyl, substituted or                unsubstituted C₁-C₆deuteroalkyl, substituted or                unsubstituted C₁-C₆heteroalkyl, substituted or                unsubstituted C₃-C₁₀cycloalkyl, substituted or                unsubstituted C₃-C₁₀deuterocycloalkyl, substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, substituted or                unsubstituted aryl, or substituted or unsubstituted                heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₃-C₁₀deuterocycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₃-C₁₀deuterocycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, —OC₁-C₆deuteroalkyl, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments,each R¹ is independently H, D, or F. In other embodiments, each R¹ isindependently H, or D. In some other embodiments, each R¹ is H.

In some embodiments, the compound has the structure of Formula (II):

In some embodiments, the compound has the structure of Formula (III):

In some embodiments, the compound has the structure of Formula (IV):

In some embodiments, R² is Br, —CN, —OH, —OC₂-C₆alkyl,—OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂,—NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂,—OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₆alkenyl, orsubstituted or unsubstituted C₂-C₆alkynyl. In some embodiments, R² isBr, substituted or unsubstituted C₂-C₆alkenyl, or substituted orunsubstituted C₂-C₆alkynyl. In some embodiments, R² is Br.

In some embodiments, R² is A-L¹-.

As used herein, unless otherwise specifically indicated, linker L¹ is tobe read in either direction. For example, when R² is A-L¹- and L¹ is—O(C₁-C₆alkylene)— then R² is either A-O(C₁-C₆alkylene)- orA-(C₁-C₆alkylene)O—.

In some embodiments, L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,C₁-C₆alkylene, —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-,—S(C₁-C₆alkylene)-, —S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-. Insome embodiments, L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—,C₁-C₆alkylene, —O(C₁-C₆alkylene)-, or —NR⁵(C₁-C₆alkylene)-. In someembodiments, L¹ is absent, —O—, —NR⁵—, C₁-C₄alkylene,—O(C₁-C₄alkylene)-, or —NR⁵(C₁-C₄alkylene)-. In some embodiments, L isabsent, —O—, —NH—, C₁-C₄alkylene, —O(C₁-C₄alkylene)-, or—NH(C₁-C₄alkylene)-. In some embodiments, L¹ is absent, —O—, —NH—,—OCH₂—, or —NHCH₂—. In some embodiments, L¹ is absent, —O—, or —OCH₂—.In some embodiments, L¹ is absent, —O—, or —NH—. In some embodiments, L¹is absent, or —O—. In some embodiments, L¹ is absent. In someembodiments, L¹ is —O—.

In some embodiments, R² is A-L¹-, where A-L¹- is A, A-O—, A-NR⁵—, A-S—,A-S═O—, A-S(═O)₂—, A-C₁-C₆alkylene, A-(C₁-C₆alkylene)O—,A-O(C₁-C₆alkylene)-, A-(C₁-C₆alkylene)NR⁵—, A-NR⁵(C₁-C₆alkylene)-,A-(C₁-C₆alkylene)S—, A-S(C₁-C₆alkylene)-, A-S═O(C₁-C₆alkylene)-,A-(C₁-C₆alkylene)S═O—, A-C₁-C₆alkylene S(═O)₂— orA-S(═O)₂C₁-C₆alkylene-. In some embodiments, R² is A-L¹-, where A-L¹- isA, A-O—, A-NR⁵—, A-C₁-C₄alkylene, A-(C₁-C₄alkylene)O—,A-O(C₁-C₄alkylene)-, A-(C₁-C₄alkylene)NR⁵—, or A-NR⁵(C₁-C₄alkylene)-. Insome embodiments, R² is A-L¹-, where A-L¹- is A, A-O—, A-NH—,A-C₁-C₄alkylene, A-(C₁-C₄alkylene)O—, or A-(C₁-C₄alkylene)NH—. In someembodiments, R² is A-L¹-, where A-L¹- is A, A-O—, A-NH—, A-CH₂, A-CH₂O—,or A-CH₂NH—. In some embodiments, R² is A-L¹-, where A-L¹- is A, A-O—,A-NH—, A-CH₂O—, or A-CH₂NH—. In some embodiments, R² is A-L¹-, whereA-L¹- is A, or A-O—. In some embodiments, R² is A-L¹-, where A-L¹- is A.In some embodiments, R² is A-L¹-, where A-L¹- is A-O—.

In some embodiments, R² is A-L¹-; L¹ is absent, —O—, —NH—, —OCH₂—, or—NHCH₂—; A is a cyclic ring that is a substituted or unsubstitutedphenyl, substituted or unsubstituted monocyclic heteroaryl, substitutedor unsubstituted C₃-C₈cycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkenyl, or substituted or unsubstitutedC₂-C₈heterocycloalkyl, wherein if A is substituted then A is substitutedwith one or more R⁶.

In some embodiments, R² is A-L¹-; L¹ is absent, or —O—; A is a cyclicring that is a substituted or unsubstituted phenyl, substituted orunsubstituted monocyclic heteroaryl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, orsubstituted or unsubstituted C₂-C₈heterocycloalkyl, wherein if A issubstituted then A is substituted with one or more R⁶.

In some embodiments, R² is A-L¹-; L¹ is absent; A is a cyclic ring thatis a substituted or unsubstituted phenyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₃-C₈cycloalkenyl, or substituted orunsubstituted C₂-C₈heterocycloalkyl, wherein if A is substituted then Ais substituted with one or more R⁶.

In some embodiments, A is a substituted or unsubstituted phenyl,substituted or unsubstituted monocyclic 6-membered heteroaryl,substituted or unsubstituted monocyclic 5-membered heteroaryl,substituted or unsubstituted C₃-C₆cycloalkyl, or substituted orunsubstituted C₂-C₁₀heterocycloalkyl, wherein if A is substituted then Ais substituted with one or more R⁶. In some embodiments, A is asubstituted or unsubstituted phenyl, substituted or unsubstitutedmonocyclic 6-membered heteroaryl, or substituted or unsubstitutedmonocyclic 5-membered heteroaryl, wherein if A is substituted then A issubstituted with one or more R⁶. In some embodiments, A is a substitutedor unsubstituted phenyl, wherein if A is substituted then A issubstituted with one or more R⁶. In some embodiments, A is a substitutedor unsubstituted monocyclic 6-membered heteroaryl, or substituted orunsubstituted monocyclic 5-membered heteroaryl, wherein if A issubstituted then A is substituted with one or more R⁶. In someembodiments, if A is substituted then A is substituted with one, two,three, or four R⁶. In some embodiments, if A is substituted then A issubstituted with one, two, or three R⁶. In some embodiments, if A issubstituted then A is substituted with one, or two R⁶. In someembodiments, if A is substituted then A is substituted with R⁶.

In some embodiments, A is a substituted or unsubstituted phenyl, whereinif A is substituted then A is substituted with one or more R⁶.

In some embodiments, A is a substituted or unsubstituted monocyclicheteroaryl, wherein if A is substituted then A is substituted with oneor more R⁶.

In some embodiments, A is a substituted or unsubstituted monocyclic5-membered heteroaryl or a substituted or unsubstituted monocyclic6-membered heteroaryl, wherein if A is substituted then A is substitutedwith one or more R⁶.

In some embodiments, A is substituted or unsubstituted monocyclicheteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, orsubstituted or unsubstituted monocyclic heteroaryl containing 0-4 Natoms and 1 O or S atoms, wherein if A is substituted then A issubstituted with one or more R⁶.

In some embodiments, A is substituted or unsubstituted monocyclicheteroaryl that is a substituted or unsubstituted furanyl, substitutedor unsubstituted thienyl, substituted or unsubstituted pyrrolyl,substituted or unsubstituted oxazolyl, substituted or unsubstitutedthiazolyl, substituted or unsubstituted imidazolyl, substituted orunsubstituted pyrazolyl, substituted or unsubstituted triazolyl,substituted or unsubstituted tetrazolyl, substituted or unsubstitutedisoxazolyl, substituted or unsubstituted isothiazolyl, substituted orunsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl,substituted or unsubstituted pyridinyl, substituted or unsubstitutedpyrimidinyl, substituted or unsubstituted pyrazinyl, substituted orunsubstituted pyridazinyl, or a substituted or unsubstituted triazinyl,wherein if A is substituted then A is substituted with one or more R⁶.

In some embodiments, A is substituted or unsubstituted C₃-C₆cycloalkyl,wherein if A is substituted then A is substituted with one or more R⁶.

In some embodiments, A is substituted or unsubstituted C₃-C₆cycloalkylthat is a substituted or unsubstituted cyclopropyl, substituted orunsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, orsubstituted or unsubstituted cyclohexyl, wherein if A is substitutedthen A is substituted with one or more R⁶.

In some embodiments, A is substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, wherein if A is substituted then A issubstituted with one or more R⁶.

In some embodiments, A is substituted or unsubstitutedC₂-C₁₀heterocycloalkyl that is substituted or unsubstitutedpyrrolidinonyl, substituted or unsubstituted oxazolidinonyl, substitutedor unsubstituted piperidinyl, substituted or unsubstituted morpholinyl,substituted or unsubstituted thiomorpholinyl, substituted orunsubstituted piperazinyl, substituted or unsubstituted aziridinyl,substituted or unsubstituted azetidinyl, substituted or unsubstitutedoxetanyl, substituted or unsubstituted thietanyl, substituted orunsubstituted homopiperidinyl, substituted or unsubstituted oxepanyl,substituted or unsubstituted thiepanyl, substituted or unsubstitutedoxazepinyl, substituted or unsubstituted diazepinyl, substituted orunsubstituted thiazepinyl, or substituted or unsubstituted1,2,3,6-tetrahydropyridinyl, wherein if A is substituted then A issubstituted with one or more R⁶.

In some embodiments, the compound has the structure of Formula (Va), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—, C₁-C₆alkylene,        —O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,        —S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-; ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl;

-   -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,        —NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4.

As used herein, unless otherwise specifically indicated, linker L¹ is tobe read in either direction. In some embodiments, L¹ is absent, —O—,—NR⁵—, C₁-C₄alkylene, —O(C₁-C₄alkylene)-, or —NR⁵(C₁-C₄alkylene)-. Insome embodiments, L¹ is absent, —O—, —NH—, C₁-C₄alkylene,—O(C₁-C₄alkylene)-, or —NH(C₁-C₄alkylene)-. In some embodiments, L¹ isabsent, —O—, —NH—, —OCH₂—, or —NHCH₂—. In some embodiments, L¹ isabsent, —O—, or —OCH₂—. In some embodiments, L¹ is absent, —O—, or —NH—.In some embodiments, L¹ is absent, or —O—. In some embodiments, L¹ isabsent. In some embodiments, L¹ is —O—.

In some embodiments, the compound has the structure of Formula (Vb), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl;

-   -   each R⁶ is independently H, D, halogen, CN, —OR⁵, —SR⁵,        —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,        —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,        —NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;        -   each R⁴ is independently a substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted aryl, or substituted or unsubstituted            heteroaryl;        -   each R⁵ is independently H, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl; or two R⁵ groups            attached to the same N atom are taken together with carbon            atom to which they are attached to form a substituted or            unsubstituted carbocycle or substituted or unsubstituted            heterocycle;    -   each R³ is independently H, D, halogen, —CN, —OH, —OC₁-C₆alkyl,        —OC₁-C₆fluoroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4.

In some embodiments, ring

is a phenyl, monocyclic 6-membered heteroaryl, monocyclic 5-memberedheteroaryl, C₃-C₆cycloalkyl, or C₂-C₁₀heterocycloalkyl.

In some embodiments, ring

is a phenyl. In some embodiments,

In some embodiments, ring

is a monocyclic 6-membered heteroaryl. In some embodiments,

In some embodiments, ring

is a monocyclic 5-membered heteroaryl. In some embodiments,

In some embodiments,

In some embodiments, ring

is C₃-C₆cycloalkyl. In some embodiments, ring

is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, ring

is C₂-C₁₀heterocycloalkyl. In some embodiments, ring

is C₂-C₁₀heterocycloalkyl that is pyrrolidinonyl, oxazolidinonyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, or 1,2,3,6-tetrahydropyridinyl.

In some embodiments, each R⁶ is independently H, D, halogen, CN, —OR⁵,—SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,—OC(═O)R⁴, —CO₂R⁵, —N(R⁵)₂, —NR⁵C(═O)R⁴, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, substitutedor unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted monocyclicC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, each R⁶ is independently H, D, halogen, CN, —OR⁵,—C(═O)R⁴, —CO₂R⁵, —N(R⁵)₂, —NR⁵C(═O)R⁴, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, substitutedor unsubstituted C₁-C₄deuteroalkyl, substituted or unsubstitutedC₁-C₄heteroalkyl, substituted or unsubstituted monocyclicC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,each R⁶ is independently H, D, halogen, CN, —OR⁵, —C(═O)R⁴, —CO₂R⁵,—N(R⁵)₂, —NR⁵C(═O)R⁴, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl,C₁-C₄heteroalkyl, monocyclic C₃-C₆cycloalkyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, each R⁶ is independently H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted monocyclicC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, the compound has the structure of Formula (VIa):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (VIb):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (VIIa):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has the structure of Formula (VIIb):

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, compounds described herein have the followingstructure:

-   -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, compounds described herein have the followingstructure:

-   -   wherein,    -   R² is as described in Table 1;    -   or a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R² is as described in Table 1.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, compounds of Formula (I) include, but are notlimited to, those described in Table 1.

TABLE 1

Compound Position Number R^(A) of R² R² 1-1  H — H 1-2  Me — H 1-3  HC-6 Br 1-4  H C-6 ethynyl 1-5  H C-6 Ph 1-6  H C-6

1-7  H C-6

1-8  H C-6

1-9  H C-6 MeO 1-10 H C-6 OH 1-11 H C-6

1-12 H C-6

1-13 H C-6

1-14 H C-6

1-15 H C-6

1-16 H C-6

1-17 H C-6

1-18 H C-6

1-19 H C-6

1-20 H C-6

1-21 H C-6

1-22 H C-6

1-23 H C-6

1-24 H C-6

1-25 H C-6

1-26 H C-6

1-27 H C-6

1-28 H C-6

1-29 H C-6

1-30 H C-6

1-31 H C-6

1-32 H C-6

1-33 H C-6

1-34 H C-6

1-35 H C-6

1-36 H C-6

1-37 H C-6

1-38 H C-6

1-39 H C-6

1-40 H C-6

1-41 H C-6

1-42 H C-6

1-43 H C-6

1-44 H C-6

1-45 H C-6

1-46 H C-6

1-47 H C-6

1-48 H C-6

1-49 H C-6

1-50 H C-6

1-51 H C-6

1-52 H C-6

1-53 H C-6

1-54 H C-6

1-55 H C-6

1-56 H C-6

1-57 H C-6

1-58 H C-6

1-59 H C-6

1-60 H C-6

1-61 H C-6

1-62 H C-6 COOH 1-63 H C-6

1-64 H C-6

1-65 H C-6

1-66 H C-6

1-67 H C-6

1-68 H C-6

1-69 H C-6

1-70 H C-6

1-71 H C-6

1-72 H C-6

1-73 H C-6

1-74 H C-6

1-75 H C-6

1-76 H C-6

1-77 H C-6

1-78 H C-6

In some embodiments, the R² substituents listed in Table 1 is attachedat C-7 or C-8 of the 2-(aminomethyl)quinolin-4(1H)-one. In someembodiments, the R² substituents listed in Table 1 is attached at C-7 ofthe 2-(aminomethyl)quinolin-4(1H)-one. In some embodiments, the R²substituents listed in Table 1 is attached at C-8 of the2-(aminomethyl)quinolin-4(1H)-one.

Compounds in Table 1 are named:

-   2-(Aminomethyl)quinolin-4(1H)-one (Compound 1-1);-   2-(Aminomethyl)-1-methylquinolin-4(1H)-one (Compound 1-2);-   2-(Aminomethyl)-6-bromoquinolin-4(1H)-one (Compound 1-3);-   2-(Aminomethyl)-6-ethynylquinolin-4(1H)-one (Compound 1-4);-   2-(Aminomethyl)-6-phenylquinolin-4(1H)-one (Compound 1-5);-   2-(Aminomethyl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-one    (Compound 1-6);-   2-(Aminomethyl)-6-(phenylethynyl)quinolin-4(1H)-one (Compound 1-7);-   2-(Aminomethyl)-6-(1H-pyrazol-1-yl)quinolin-4(1H)-one (Compound    1-8);-   2-(Aminomethyl)-6-methoxyquinolin-4(1H)-one (Compound 1-9);-   2-(Aminomethyl)-6-hydroxyquinolin-4(1H)-one (Compound 1-10);-   2-(Aminomethyl)-6-(4-fluorophenyl)quinolin-4(1H)-one (Compound    1-11);-   2-(Aminomethyl)-6-(3-fluorophenyl)quinolin-4(1H)-one (Compound    1-12);-   2-(Aminomethyl)-6-(2-fluorophenyl)quinolin-4(1H)-one (Compound    1-13);-   2-(Aminomethyl)-6-(1H-1,2,3-triazol-1-yl)quinolin-4(1H)-one    (Compound 1-14);-   2-(Aminomethyl)-6-(2H-tetrazol-2-yl)quinolin-4(1H)-one (Compound    1-15);-   2-(Aminomethyl)-6-(1H-tetrazol-1-yl)quinolin-4(1H)-one (Compound    1-16);-   2-(Aminomethyl)-6-(2-methyl-2H-tetrazol-5-yl)quinolin-4(1H)-one    (Compound 1-17);-   2-(Aminomethyl)-6-((4-fluorophenyl)ethynyl)quinolin-4(1H)-one    (Compound 1-18);-   2-(Aminomethyl)-6-((3-fluorophenyl)ethynyl)quinolin-4(1H)-one    (Compound 1-19);-   2-(Aminomethyl)-6-((2-fluorophenyl)ethynyl)quinolin-4(1H)-one    (Compound 1-20);-   2-(Aminomethyl)-6-phenoxyquinolin-4(1H)-one (Compound 1-21);-   2-(Aminomethyl)-6-(2-fluorophenoxy)quinolin-4(1H)-one (Compound    1-22);-   2-(Aminomethyl)-6-(3-fluorophenoxy)quinolin-4(1H)-one (Compound    1-23);-   2-(Aminomethyl)-6-(4-fluorophenoxy)quinolin-4(1H)-one (Compound    1-24);-   2-(Aminomethyl)-6-(benzyloxy)quinolin-4(1H)-one (Compound 1-25);-   2-(Aminomethyl)-6-((2-fluorobenzyl)oxy)quinolin-4(1H)-one (Compound    1-26);-   2-(Aminomethyl)-6-((3-fluorobenzyl)oxy)quinolin-4(1H)-one (Compound    1-27);-   2-(Aminomethyl)-6-((4-fluorobenzyl)oxy)quinolin-4(1H)-one (Compound    1-28);-   2-(Aminomethyl)-6-(phenylamino)quinolin-4(1H)-one (Compound 1-29);-   2-(Aminomethyl)-6-(benzylamino)quinolin-4(1H)-one (Compound 1-30);-   2-(Aminomethyl)-6-(prop-2-yn-1-yloxy)quinolin-4(1H)-one (Compound    1-31);-   2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)oxy)quinolin-4(1H)-one    (Compound 1-32);-   2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)oxy)quinolin-4(1H)-one    (Compound 1-33);-   2-(Aminomethyl)-6-(prop-2-yn-1-ylamino)quinolin-4(1H)-one (Compound    1-34);-   2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)amino)quinolin-4(1H)-one    (Compound 1-35);-   2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)amino)quinolin-4(1H)-one    (Compound 1-36);-   2-(Aminomethyl)-6-(pyridin-2-yl)quinolin-4(1H)-one (Compound 1-37);-   2-(Aminomethyl)-6-(pyridin-3-yl)quinolin-4(1H)-one (Compound 1-38);-   2-(Aminomethyl)-6-(pyridin-4-yl)quinolin-4(1H)-one (Compound 1-39);-   2-(Aminomethyl)-6-(pyrimidin-5-yl)quinolin-4(1H)-one (Compound    1-40);-   2-(Aminomethyl)-6-(pyrazin-2-yl)quinolin-4(1H)-one (Compound 1-41);-   2-(Aminomethyl)-6-(oxazol-2-yl)quinolin-4(1H)-one (Compound 1-42);-   2-(Aminomethyl)-6-(thiazol-2-yl)quinolin-4(1H)-one (Compound 1-43);-   2′-(Aminomethyl)-[2,6′-biquinolin]-4′(1′H)-one (Compound 1-44);-   2′-(Aminomethyl)-[3,6′-biquinolin]-4′(1′H)-one (Compound 1-45);-   2-(Aminomethyl)-6-(5-methyl-2-oxopyridin-1(2H)-yl)quinolin-4(1H)-one    (Compound 1-46);-   2-(Aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinolin-4(1H)-one    (Compound 1-47);-   2-(Aminomethyl)-6-(1-phenyl-1H-pyrazol-4-yl)quinolin-4(1H)-one    (Compound 1-48);-   2-(Aminomethyl)-6-(4-phenyl-1H-pyrazol-1-yl)quinolin-4(1H)-one    (Compound 1-49);-   2-(Aminomethyl)-6-((1-methyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one    (Compound 1-50);-   2-(Aminomethyl)-6-((1-phenyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one    (Compound 1-51);-   2-(Aminomethyl)-6-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one-   (Compound 1-52);-   2-(Aminomethyl)-6-((1-(3-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one-   (Compound 1-53);-   2-(Aminomethyl)-6-((1-(4-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one-   (Compound 1-54);-   2′-(Aminomethyl)-3,4-dihydro-2H-[1,6′-biquinolin]-4′(1′H)-one    (Compound 1-55);-   2-(Aminomethyl)-6-(4-phenylpiperazin-1-yl)quinolin-4(1H)-one    (Compound 1-56);-   2-(Aminomethyl)-6-(pyrrolidine-1-carbonyl)quinolin-4(1H)-one    (Compound 1-57);-   2-(Aminomethyl)-6-((3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one-   (Compound 1-58);-   2-(Aminomethyl)-6-((3R,4R)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one-   (Compound 1-59);-   2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxamide (Compound    1-60);-   2-(Aminomethyl)-N-methyl-4-oxo-1,4-dihydroquinoline-6-carboxamide    (Compound 1-61);-   2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxylic acid    (Compound 1-62);-   2-(Aminomethyl)-6-isopropoxyquinolin-4(1H)-one (Compound 1-63);-   2-(Aminomethyl)-6-isobutoxyquinolin-4(1H)-one (Compound 1-64);-   2-(Aminomethyl)-[6,8′-biquinolin]-4(1H)-one (Compound 1-65);-   2-(Aminomethyl)-6-(5-(benzyloxy)pyridin-3-yl)quinolin-4(1H)-one    (Compound 1-66);-   2-(Aminomethyl)-6-(4-chlorophenyl)quinolin-4(1H)-one (Compound    1-67);-   2-(Aminomethyl)-6-(3-chlorophenyl)quinolin-4(1H)-one (Compound    1-68);-   2-(Aminomethyl)-6-(2-chlorophenyl)quinolin-4(1H)-one (Compound    1-69);-   2-(Aminomethyl)-6-(2-chloro-4-fluorophenyl)quinolin-4(1H)-one    (Compound 1-70);-   2-(Aminomethyl)-6-(4-chloro-2-fluorophenyl)quinolin-4(1H)-one    (Compound 1-71);-   2-(Aminomethyl)-6-(3-fluoro-4-methoxyphenyl)quinolin-4(1H)-one    (Compound 1-72);-   2-(Aminomethyl)-6-(2-fluoro-4-methoxyphenyl)quinolin-4(1H)-one    (Compound 1-73);-   2-(Aminomethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one    (Compound 1-74);-   2-(Aminomethyl)-6-(5-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one    (Compound 1-75);-   2-(Aminomethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one    (Compound 1-76);-   2-(Aminomethyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-4(1H)-one    (Compound 1-77);-   2-(Aminomethyl)-6-(2-methoxyethoxy)quinolin-4(1H)-one (Compound    1-78);    or a pharmaceutically acceptable salt, or solvate thereof.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In some embodiments, the compounds describedherein exist in unsolvated or in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers to a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material is administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with an acid. In some embodiments,the compound described herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethylfumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid;nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid;phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylicacid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaricacid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenicacid.

In some embodiments, a compound described herein is prepared as achloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt,citrate salt or phosphate salt. In some embodiments, a compounddescribed herein is prepared as a hydrochloride salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with a base. In some embodiments,the compound described herein is acidic and is reacted with a base. Insuch situations, an acidic proton of the compound described herein isreplaced by a metal ion, e.g., lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, or tris(hydroxymethyl)methylamine.In other cases, compounds described herein form salts with amino acidssuch as, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt, or ammonium salt. In some embodiments, the compounds providedherein are prepared as a sodium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds described herein, aswell as active metabolites of these compounds having the same type ofactivity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds described herein are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize, or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by other means, including,but not limited to, the use of chromophores or fluorescent moieties,bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns. In certain embodiments, compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds/salts,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, resolution of enantiomers is carriedout using covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. In some instances, a prodrug is a substrate for atransporter. Further or alternatively, the prodrug also has improvedsolubility in pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. A furtherexample of a prodrug is a short peptide (polyaminoacid) bonded to anacid group where the peptide is metabolized to reveal the active moiety.In certain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38. In someembodiments, a hydroxyl group in the compounds disclosed herein is usedto form a prodrug, wherein the hydroxyl group is incorporated into anacyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, arylester, phosphate ester, sugar ester, ether, and the like. In someembodiments, a hydroxyl group in the compounds disclosed herein is aprodrug wherein the hydroxyl is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, a carboxyl group is used toprovide an ester or amide (i.e. the prodrug), which is then metabolizedin vivo to provide a carboxylic acid group. In some embodiments,compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound described herein as set forthherein are included within the scope of the claims. In some cases, acompound described herein is a prodrug for another derivative or activecompound.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds of Formula (I) described herein are synthesized using standardsynthetic techniques or using methods known in the art in combinationwith methods described herein. Unless otherwise indicated, conventionalmethods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6^(th) Edition, John Wiley and Sons, Inc. Alternative reactionconditions for the synthetic transformations described herein may beemployed such as variation of solvent, reaction temperature, reactiontime, chemical reagents and other reaction conditions. The startingmaterials are available from commercial sources or are readily prepared.

4-Quinolones are prepared using well known synthetic routes (see Methodsof synthesis, modification and biological activity of 4-quinolones(review); A. A. Boteva and O. P. Krasnykh, Chemistry of HeterocyclicCompounds 2009, 45, pp 757-785 and references cited therein) and theseare further functionalized to provide substituted 4-quinolones using avariety of methods.

In some embodiments, 2-(aminomethyl)-4-quinolones are synthesized asshown in Scheme 1. Anilines of general structure 1-1 can be converted tothe corresponding ortho-acyl-anilines 1-2, via treatment of 1-1 with thecorresponding acyl chloride in the presence of AlCl₃, and in a suitablesolvent with or without heating (Freidel-Crafts Acylation).Alternatively, 1-2 may be prepared via treatment of 1-1 with thecorresponding alkylnitrile in the presence of AlCl₃ and/or BCl₃, in asolvent such as toluene or 1,2-dichloroethane, with or without heating.Compound 1-2 may be converted to the 2,4-diketobutanoate esterderivative 1-3, via reaction with, for example, diethyl oxalate in thepresence of a base such as NaOEt. Acid catalyzed cyclization thenaffords the 4-quinolone 1-4 as the ester or acid (R⁴=Et or H) (see S. C.W. Coltman et al, Synthesis 1984, 2, pp 150-152), which can be reducedto the alcohol 1-5. The reduction may be accomplished via, for example,formation of the mixed anhydride by treating the acid with ethylchloroformate in an organic solvent such as THF in the presence of amild base such as Et₃N. Subsequent reaction with a reducing agent suchas NaBH₄ then yields the alcohol 1-5. Alternatively, alcohol 1-5 may beobtained via treatment of ester 1-4 with CoCl₂ and NaBH₄ in a mixture ofTHF and MeOH.

Transformation of the alcohol of 1-5 to the amine 1-8 may be achievedusing a variety of methods. One route is to convert the alcohol to thecorresponding chloride 1-6 (e.g. by reaction with thionyl chloride in asolvent such as CH₂Cl₂) followed by displacement with azide ion (e.g.NaN₃ in a polar solvent such as DMF) to give 1-7. Alternatively, alcohol1-5 may be directly converted to azide 1-7 using, for example,diphenylphosphoroyl azide in the presence of a base such as DBU, and ina solvent such as 1,4-dioxane. Reduction of the azide 1-7 using theStaudinger reaction (reaction with PPh₃ in a solvent such as THF/H₂O)then affords the amine 1-8.

Alternatively, amine 1-8 can be prepared from 4-quinolone-2-carboxylicacid 1-4 (R⁴═H). For example, treatment of 1-4 (R⁴═H) with NH₄Cl in thepresence of a base and a peptide-coupling agent such as HATU, or EDCIand HOBt yields carboxamide derivatives 1-9. Reduction of thecarboxamide (of 1-9) using agents such as BH₃.DMS in THF, gives amine1-8.

In some embodiments, 2-(aminomethyl)-4-quinolones are synthesized asshown in Scheme 2. Ortho-acyl-anilines of general structure 2-1 can bereacted with, for example, acetyl chloride or acetic anhydride in thepresence of a mild organic base such as Et₃N in a solvent such as THF togive the acetamide 2-2. Intramolecular ring-closure using a base (e.g.NaOH, or KO^(t)Bu, or LiH) in a suitable solvent, provide the2-methyl-4-quinolones 2-3. Halogenation of the 2-methyl substituent canbe achieved using a variety of methods to afford 2-4 (Y═Cl, Br or I).For example, treatment of 2-3 with NBS in CCl₄ using benzoyl peroxide asa catalyst will provide 2-4 where Y═Br. Compound 2-4 can be transformedinto the 2-aminomethyl derivative 2-5 using routes described in Scheme 1

In some embodiments, 2-(aminomethyl)-4-quinolones are synthesized asshown in Scheme 3. Anilines of general structure 3-1 may be condensedwith ethyl acetoacetate in the presence of an acid (e.g. acetic acid orHCl) and in a suitable solvent such as toluene, with or without heating,to give intermediate 3-2, which may be converted to2-methyl-4-quinolones 3-3 by heating in the presence of an acid such assulfuric acid, or Eaton's Reagent (Conrad-Limpach Reaction).Alternatively, intermediate 3-2 may be obtained via condensation of 3-1with ethyl acetoacetate in the presence of an organometallic reagentsuch as iron (III) trifluoromethanesulfonate or nickel diacetate, withor without heating (C.-L. Feng et al, Chemical Papers 2014, 68, pp1097-1103). In a similar manner, anilines 3-1 may be converted tointermediate 3-4 via treatment with an alkyl acetylenedicarboxylate 3-7,in a suitable solvent such as MeOH, with or without heating. Theintermediate 3-4 can then be cyclized under acidic conditions (using forexample PPA, or Eaton's Reagent) to afford 4-quinolone-2-carboxylicesters 3-5. Both 3-3 and 3-5 may be converted to the2-(aminomethyl)-4-quinolone 3-6 using the procedures described inSchemes 1 and 2.

In some embodiments, 2-(aminomethyl)-4-quinolones are synthesized asshown in Scheme 4. Ortho-acyl-anilines of general structure 4-1 can bereacted with an alkyl 2-chloro-2-oxoacetate in the presence of a mildorganic base such as pyridine or Et₃N, and in a solvent such as THF togive intermediate 4-2. Intramolecular ring-closure using a base (e.g.K₂CO₃, or DBU) in a suitable solvent (e.g. MeOH or EtOH), provide the4-quinolones 4-3. Compound 4-3 can be transformed into the2-(aminomethyl)-4-quinolones 4-4 using routes described in Scheme 1.

In some embodiments, 2-(aminomethyl)-4-quinolones are synthesized asshown in Scheme 5. The treatment of acetylenic arylketone derivatives5-1 with primary amines, in presence of K₃PO₄.3H₂O and DMSO as solvent,give 2-methyl-4-quinolone derivatives 5-2 (J. Shao et al, Synthesis2012, 44, pp 1798-1808). Intermediate 5-2 can be transformed into2-(aminomethyl)-4-quinolones 5-3 using routes described in Scheme 2.

Palladium mediated carbonylation of ortho-iodoanilines of structure 6-1in the presence of terminal acetylenes affords2-substituted-4-quinolones of general structure 6-2 (Scheme 6; S. Toriiet al, Tetrahedron 1993, 49, pp 6773-6784).

In some embodiments, compounds are prepared as described in theExamples.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkylene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃,and —CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl.Non-limiting examples of an alkynyl group include —C═CH,—C═CCH₃—C═CCH₂CH₃, —CH₂C≡CH.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term “aromatic” refers to a planar ring having a delocalizedr-electron system containing 4n+2 π electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₀aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring does not contain two adjacentO or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 10 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 10 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused withan aryl or heteroaryl. In some embodiments, the heterocycloalkyl isoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidin-2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The termheteroalicyclic also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

A pharmaceutical combination is a product that results from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that the active ingredients, e.g. a compounddescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, and a co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, and a co-agent, are administered to a patient asseparate entities either simultaneously, concurrently or sequentiallywith no specific intervening time limits, wherein such administrationprovides effective levels of the two compounds in the body of thepatient. The latter also applies to cocktail therapy, e.g. theadministration of three or more active ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long-acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch.

The powder composition may be presented in unit dosage form, in forexample, capsules, cartridges, gelatin or blister packs from which thepowder may be administered with the aid of an inhalator or insufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds described herein, or a pharmaceuticallyacceptable salt, or solvate thereof, are used in the preparation ofmedicaments for the treatment of diseases or conditions in a mammal thatwould benefit from inhibition or reduction of LOXL2 activity.

Methods for treating any of the diseases or conditions described hereinin a mammal in need of such treatment involve administration ofpharmaceutical compositions that include at least one compound describedherein or a pharmaceutically acceptable salt, active metabolite,prodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, in order toprevent a return of the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, are from about 0.01 to about 50 mg/kg per body weight. In someembodiments, the daily dosage or the amount of active in the dosage formare lower or higher than the ranges indicated herein, based on a numberof variables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt, or solvate thereof, is: (a)systemically administered to the mammal; and/or (b) administered orallyto the mammal; and/or (c) intravenously administered to the mammal;and/or (d) administered by injection to the mammal; and/or (e)administered topically to the mammal; and/or (f) administerednon-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain instances, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, in combination with one or more other therapeuticagents. In certain embodiments, the pharmaceutical composition furthercomprises one or more anti-cancer agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, is co-administeredwith a second therapeutic agent, wherein the compound described herein,or a pharmaceutically acceptable salt, or solvate thereof, and thesecond therapeutic agent modulate different aspects of the disease,disorder or condition being treated, thereby providing a greater overallbenefit than administration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may be additiveof the two therapeutic agents or the patient may experience asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens isoptionally determined by means similar to those set forth hereinabovefor the actives themselves. Furthermore, the methods ofprevention/treatment described herein encompasses the use of metronomicdosing, i.e., providing more frequent, lower doses in order to minimizetoxic side effects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, is initiated prior to, during, or after treatment with a secondagent described herein, and continues until any time during treatmentwith the second agent or after termination of treatment with the secondagent. It also includes treatments in which a compound described herein,or a pharmaceutically acceptable salt, or solvate thereof, and thesecond agent being used in combination are administered simultaneouslyor at different times and/or at decreasing or increasing intervalsduring the treatment period. Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable salt,or solvate thereof, as well as combination therapies, are administeredbefore, during or after the occurrence of a disease or condition, andthe timing of administering the composition containing a compoundvaries. Thus, in one embodiment, the compounds described herein are usedas a prophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length of time required for treatmentvaries, and the treatment length is adjusted to suit the specific needsof each subject. For example, in specific embodiments, a compounddescribed herein or a formulation containing the compound isadministered for at least 2 weeks, about 1 month to about 5 years.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt, or solvate thereof, is administered in combination withchemotherapy, hormone blocking therapy, radiation therapy, monoclonalantibodies, or combinations thereof.

Chemotherapy includes the use of anti-cancer agents.

In one aspect, the compound described herein, or a pharmaceuticallyacceptable salt, or solvate thereof, is administered or formulated incombination with one or more anti-cancer agents.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1: Synthesis of 2-(aminomethyl)quinolin-4(1H)-one hydrochloride(Compound 1-1)

Step 1: 4-Oxo-1,4-dihydroquinoline-2-carboxamide (2)

To a stirred solution of 4-oxo-1,4-dihydroquinoline-2-carboxylic acid 1(500 mg, 2.64 mmol) in DMF (10 mL) at 0° C., were added EDCIhydrochloride (761 mg, 3.97 mmol), HOBt (536 mg, 3.97 mmol),N-methylmorpholine (0.87 mL, 7.94 mmol) and NH₄Cl (708 mg, 13.23 mmol).The reaction mixture was warmed to RT and stirred for 20 h. The reactionmixture was diluted with water (20 mL) and extracted with EtOAc (2×30mL). The combined organic extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordcompound 2 (330 mg, 66%) as an off white solid, that did not requirefurther purification. LCMS Mass: 188.9 (M⁺+1).

Step 2: tert-Butyl ((4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate (3)

To a stirred solution of compound 2 (330 mg, 1.75 mmol) in anhydrous THF(20 mL) at 0° C. under an inert atmosphere, was added BH₃.DMS (5 Msolution in ether, 1.05 mL, 5.26 mmol) drop-wise. The reaction mixturewas refluxed for 20 h. The mixture was cooled to 0° C., and to this wasadded aq. 2 N HCl (10 mL). The mixture was heated at 50° C. for 30 min.After cooling to RT, the aqueous layer was separated and washed withEtOAc (20 mL). The pH of the aq. layer was adjusted to ˜8 with saturatedaq. Na₂CO₃ solution. To this aq. layer was added (Boc)₂O (0.6 mL, 2.63mmol) and the mixture stirred at RT for 16 h. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified (silica gel; eluting with 6% EtOAc in hexanes), to affordcompound 3 (80 mg, 17%) as pale yellow oil. ¹H NMR (500 MHz, CDCl₃): δ8.15 (br s, 1H), 8.06 (br d, J=8.1 Hz, 1H), 7.77 (br t, J=7.5 Hz, 1H),7.59 (br t, J=7.5 Hz, 1H), 7.46 (m, 1H), 5.99 (br s, 1H), 4.66 (br d,J=4.6 Hz, 2H), 1.49 (s, 9H). LCMS Mass: 274.9 (M⁺+1).

Step 3: 2-(Aminomethyl)quinolin-4(1H)-one hydrochloride (Compound 1-1)

To a stirred solution of compound 3 (80 mg, 0.29) in CH₂Cl₂ (2 mL) at 0°C., was added 4 M HCl in 1,4-dioxane (1 mL). The reaction mixture waswarmed to RT and stirred for 1 h. The mixture was concentrated underreduced pressure. The residue was purified via trituration with Et₂O(2×2 mL) and dried under vacuum to afford compound 1-1 (42 mg, 69%) aspale yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 12.23 (br s, 1H), 8.49 (br s, 3H), 8.09 (d,J=7.8 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.63 (m, 1H), 7.40 (m, 1H), 6.32(br s, 1H), 4.14 (br s, 2H). LCMS Mass: 175.2 (M⁺+1).

Example 2: Synthesis of 2-(aminomethyl)-1-methylquinolin-4(1H)-onehydrochloride (Compound 1-2)

Step 1: Dimethyl 2-(methyl(phenyl) amino) maleate (2)

To a stirred solution of N-methylaniline 1 (5 g, 46.73 mmol) in water(100 mL) at 0° C., was added dimethyl acetylenedicarboxylate (4.58 mL,37.38 mmol). The reaction mixture was warmed to RT and stirred for 2 h.The mixture was diluted with EtOAc (150 mL), washed with water (100 mL),then brine (40 mL). The organic layer was separated, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; eluting with 10-20% EtOAc in hexanes), to affordcompound 2 (8 g, 69%) as pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ7.37-7.44 (m, 2H), 7.30 (m, 1H), 7.19-7.24 (m, 2H), 4.80 (s, 1H), 3.52(s, 6H), 3.19 (s, 3H); LCMS Mass: 250.0 (M⁺+1).

Step 2: Methyl 1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (3)

To stirred polyphosphoric acid (81.44 g, 240.96 mmol) at 0° C., wasadded compound 2 (4 g, 16.06 mmol) portion-wise. The reaction mixturewas heated at 80° C. for 2 h. The reaction mixture was poured intoice-cold water (150 mL), and the pH was adjusted to ˜8 with Na₂CO₃. Themixture was extracted with EtOAc (2×80 mL), and the combined organicextracts were washed with brine (40 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified viatrituration with n-pentane (2×20 mL) to afford compound 3 (2.2 g, 63%)as pale yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 8.18 (d, 0.1=7.8 Hz, 1H), 7.83 (d, 0.1=3.2Hz, 2H), 7.47 (m, 1H), 6.38 (s, 1H), 3.96 (s, 3H), 3.79 (s, 3H); LCMSMass: 218.0 (M+1).

Step 3: 2-(Hydroxymethyl)-1-methylquinolin-4(1H)-one (4)

To a stirred solution of compound 3 (1 g, 4.61 mmol) in THF/MeOH (1:1,20 mL) at 0° C. under an inert atmosphere, were added CoCl₂ (1.02 g,9.22 mmol) followed by NaBH₄ (700 mg, 18.43 mmol) portion-wise. Thereaction mixture was warmed to RT and stirred for 1 h. The mixture wasfiltered through a pad of celite and the filtrate was concentrated underreduced pressure. The residue was diluted with water (25 mL) andextracted with EtOAc (2×40 mL). The combined organic extracts werewashed with brine (20 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to afford compound 4 (650 mg) as pale yellowsolid, which was used without further purification.

¹H NMR (500 MHz, DMSO-d₆): δ 8.16 (dd, J=8.0, 1.3 Hz, 1H), 7.70-7.80 (m,2H), 7.37 (t, J=7.4 Hz, 1H), 6.23 (s, 1H), 5.74 (t, J=5.6 Hz, 1H), 4.59(d, J=5.8 Hz, 2H), 3.72 (s, 3H); LCMS Mass: 190.2 (M⁺+1).

Step 4: 2-(Azidomethyl)-1-methylquinolin-4(1H)-one (5)

To a stirred solution of compound 4 (200 mg, crude) in 1,4-dioxane (10mL) at RT under an inert atmosphere, were added DBU (0.48 mL, 3.17 mmol)and DPPA (0.69 mL, 3.17 mmol). The mixture was stirred at RT for 16 h.The reaction mixture was diluted with water (20 mL) and extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brine(15 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified (silica gel; eluting with 2% MeOH inDCM), to afford compound 5 (140 mg) as pale yellow oil, which was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (dd,J=8.0, 1.3 Hz, 1H), 7.79 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 6.27 (s,1H), 4.73 (s, 2H), 3.74 (s, 3H); LCMS Mass: 214.8 (M⁺+1).

Step 5: 2-(Aminomethyl)-1-methylquinolin-4(1H)-one (6)

To a stirred solution of compound 5 (140 mg, 0.65 mmol) in a mixture ofTHF/methanol (1:1, 8 mL) at 0° C. under an inert atmosphere, was addedtriphenylphosphine (257 mg, 0.98 mmol) portion-wise. The reactionmixture was warmed to RT and stirred for 48 h. The mixture was dilutedwith water (20 mL) and washed with Et₂O (2×10 mL). The organic layer wasseparated and the aqueous layer was concentrated under reduced pressureto afford compound 6 (60 mg) as pale yellow solid, which was usedwithout further purification. ¹H NMR (500 MHz, DMSO-d₆): δ 8.16 (d,J=7.8 Hz, 1H), 7.78 (m, 1H), 7.72 (m, 1H), 7.36 (m, 1H), 6.24 (s, 1H),3.83 (s, 2H), 3.75 (s, 3H), 2.05 (br s, 2H); LCMS Mass: 188.9 (M⁺+1).

Step 6: 2-(Aminomethyl)-1-methylquinolin-4(1H)-one hydrochloride(Compound 1-2)

To a stirred solution of compound 6 (50 mg, crude) in CH₂Cl₂(3 mL) at 0°C., was added HCl (2M HCl in Et₂O, 1 mL, 2 mmol). The mixture wasstirred at RT for 10 min. The mixture was concentrated under reducedpressure. The residue was purified via trituration with Et₂O (2×5 mL)and dried under vacuum to afford compound 1-2 (57 mg, 39% over twosteps) as pale brown solid.

¹H NMR (500 MHz, DMSO-d₆): δ 8.82 (br s, 3H), 8.22 (dd, J=7.8, 1.2 Hz,1H), 7.94 (d, J=8.7 Hz, 1H), 7.85 (m, 1H), 7.49 (t, 0.1=7.5 Hz, 1H),6.41 (s, 1H), 4.38 (d, 0.1=5.2 Hz, 2H), 3.83 (s, 3H); LCMS Mass: 189.3(M⁺+1).

Example 3: Synthesis of 2-(aminomethyl)-6-bromoquinolin-4(1H)-onehydrochloride (Compound 1-3)

Step 1: 6-Bromo-4-oxo-1,4-dihydroquinoline-2-carboxamide (2)

The title compound (2) was prepared from6-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid 1 using theprocedure described for Example 1, Step 1. LCMS Mass: 264.9 (M⁺−1).

Step 2: tert-Butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate (3)

The title compound (3) (750 mg, 36%) was prepared from compound 2 usingthe procedure described for Example 1, Step 2. ¹H NMR (500 MHz,DMSO-d₆): δ 8.08 (d, J=1.2 Hz, 1H), 7.95-7.97 (m, 2H), 7.57 (br t, J=5.9Hz, 1H), 7.46 (s, 1H), 4.39 (br d, J=5.8 Hz, 2H), 1.42 (s, 9H); LCMSMass: 353.2 (M⁺+1).

Step 3: 2-(Aminomethyl)-6-bromoquinolin-4(1H)-one hydrochloride(Compound 1-3)

To a stirred solution of compound 3 (70 mg, 0.2 mmol) in CH₂Cl₂ (1 mL)at 0° C., was added HCl (2M in Et₂O, 1 mL, 2 mmol). The reaction mixturewas warmed to RT and stirred for 2 h. The mixture was concentrated underreduced pressure. The residue was purified via trituration with Et₂O(2×2 mL) and dried under vacuum to afford compound 1-3 (20 mg, 35%) aspale yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 12.69 (br s, 1H), 8.60 (br s, 3H), 8.15 (s,1H), 7.84 (dd, J=9.0, 2.0 Hz, 1H), 7.62 (br d, J=8.4 Hz, 1H), 6.35 (brs, 1H), 4.11-4.14 (m, 2H); LCMS Mass: 253.1 (M⁺+1).

Example 4: Synthesis of 2-(aminomethyl)-6-ethynylquinolin-4(1H)-onehydrochloride (Compound 1-4)

Step 1: tert-Butyl((4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinolin-2-yl)methyl)carbamate(2)

To a stirred solution of tert-butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (300 mg,0.85 mmol) (from Example 3, Step 2) in TEA (10 mL) at RT under an inertatmosphere, were added CuI (161 mg, 0.85 mmol) and Pd(PPh₃)₂Cl₂ (30 mg,0.04 mmol). The reaction mixture was degassed under argon for 10 min.Trimethylsilylacetylene (1.45 mL, 10.2 mmol) was added and the mixtureheated at reflux for 3 days. The mixture was diluted with water (30 mL)and filtered through a pad of celite. The filtrate was extracted withEtOAc (2×30 mL). The organic layer was washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified (silica gel; eluting with 10% EtOAc in hexanes), to affordcompound 2 (45 mg, 14%) as colorless viscous syrup. ¹H NMR (400 MHz,CD₃OD): δ 8.03 (d, J=1.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.77 (dd,J=8.7, 1.7 Hz, 1H), 7.54 (s, 1H), 4.51 (s, 2H), 1.61 (s, 9H), 0.28 (s,9H); LCMS Mass: 371.1 (M⁺+1).

Step 2: tert-Butyl((6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate (3)

To a stirred solution of compound 2 (200 mg, 0.54 mmol) in methanol (5mL) at 0° C., was added K₂CO₃ (373 mg, 2.7 mmol). The mixture was warmedto RT and stirred for 4 h. The reaction mixture was concentrated underreduced pressure. The residue was poured into ice-cold water (20 mL),neutralized with citric acid and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with brine (15 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by preparative HPLC [X-select CSH C-18 reverse-phase column(250×19 mm, 5 μm); eluting with 5-90% ACN in 5 mM aq. NH₄HCO₃ over 35min; flow rate 15 mL/min] to afford compound 3 (28 mg, 17%) as paleyellow solid. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=1.8 Hz, 1H), 7.79(dd, J=8.7, 1.9 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 6.43 (s, 1H), 4.34 (s,2H), 3.62 (s, 1H), 1.48 (s, 9H); LCMS Mass: 298.9 (M⁺+1).

Step 3: 2-(Aminomethyl)-6-ethynylquinolin-4(1H)-one hydrochloride(Compound 1-4)

To a stirred solution of compound 3 (30 mg, 0.1 mmol) in CH₂Cl₂ (2 mL)at 0° C., was added HCl (2M in Et₂O, 1 mL, 2 mmol). The reaction mixturewas warmed to RT and stirred for 2 h. The mixture was concentrated underreduced pressure. The residue was purified via trituration with Et₂O(2×2 mL) and dried under vacuum to afford compound 1-4 (21 mg, 91%) aswhite solid.

¹H NMR (400 MHz, CD₃OD): δ 8.38 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.7, 1.8Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 6.73 (s, 1H), 4.36 (s, 2H), 3.72 (s,1H); LCMS Mass: 199.2 (M⁺+1).

Example 5: Synthesis of 2-(aminomethyl)-6-phenylquinoin-4(1H)-onehydrochloride (Compound 1-5)

Step 1: tert-Butyl((4-oxo-6-phenyl-1,4-dihydroquinolin-2-yl)methyl)carbamate (2)

To a stirred solution of tert-butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (200 mg,0.57 mmol) (from Example 3, Step 2) in DMF/Water (3:2, 10 mL) at RTunder an inert atmosphere, were added phenylboronic acid (69 mg, 0.57mmol) and K₂CO₃ (313 mg, 2.27 mmol). The mixture was degassed underargon for 10 min. Pd(PPh₃)₄(33 mg, 0.03 mmol) was added and the mixturewas further degassed under argon for 10 min. The reaction mixture wassealed and heated at 80° C. for 4 h. The mixture was diluted with water(20 mL) and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with brine (15 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified (silicagel; eluting with 3% MeOH in DCM), to afford compound 2 (90 mg, 45%) asan off white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.40 (br s, 1H), 8.26(d, J=1.7 Hz, 1H), 7.97 (m, 1H), 7.63-7.78 (m, 3H), 7.45-7.55 (m, 2H),7.28-7.39 (m, 2H), 5.95 (s, 1H), 4.14 (br d, J=5.8 Hz, 2H), 1.41 (s,9H); LCMS Mass: 350.9 (M⁺+1).

Step 2: 2-(Aminomethyl)-6-phenylquinolin-4(1H)-one hydrochloride(Compound 1-5)

The title compound (1-5) (40 mg, 100%) was prepared from compound 2using the procedure described for Example 1, Step 3. ¹H NMR (500 MHz,DMSO-d₆): δ 12.60 (br s, 1H), 8.60 (br s, 3H), 8.32 (d, J=2.0 Hz, 1H),8.06 (dd, J=8.7, 2.0 Hz, 1H), 7.72-7.77 (m, 3H), 7.50 (t, J=7.7 Hz, 2H),7.39 (m, 1H), 6.40 (br s, 1H), 4.15-4.19 (m, 2H); LCMS Mass: 250.9(M⁺+1).

Example 6: Synthesis of2-(aminomethyl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-onehydrochloride (Compound 1-6)

Step 1: tert-Butyl((4-oxo-6-(1-phenyl-1H-1,2,3-triazol-4-yl)-1,4-dihydroquinolin-2-yl)methyl)carbamate(2)

To a stirred solution of tert-butyl((6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (28 mg,0.09 mmol) (from Example 4, Step 2) in tert-butanol/water (1:2, 3 mL) atRT, were added CuSO₄ (1 mg, 0.0009 mmol), benzoic acid (1 mg, 0.009mmol), sodium-L-(+)-ascorbate (1 mg, 0.002 mmol) followed by azidobenzene (0.5 M in MTBE, 0.19 mL, 0.1 mmol). The mixture was stirred atRT under an inert atmosphere for 3 days. The reaction mixture wasdiluted with water (10 mL) and extracted with EtOAc (2×10 mL). Thecombined organic extracts were washed with brine (5 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified (silica gel; eluting with 1% MeOH in DCM), to afford compound 2(20 mg) as an off white solid, which was not purified further. LCMSMass: 418.1 (M⁺+1).

Step 2:2-(Aminomethyl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-onehydrochloride (Compound 1-6)

The title compound (1-6) (8 mg, 50%) was prepared from compound 2 usingthe procedure described for Example 1, Step 3. ¹H NMR (400 MHz, CD₃OD):δ 9.12 (s, 1H), 8.84 (d, J=1.6 Hz, 1H), 8.45 (dd, J=8.8, 2.0 Hz, 1H),7.95-7.99 (m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.62-7.67 (m, 2H), 7.56 (m,1H), 6.67 (s, 1H), 4.35 (s, 2H); LCMS Mass: 316.1 (M⁺- 1).

Example 7: Synthesis of2-(aminomethyl)-6-(phenylethynyl)quinolin-4(1H)-one hydrochloride(Compound 1-7)

Step 1: tert-Butyl((6-bromo-4-((tert-butoxycarbonyl)oxy)quinolin-2-yl)methyl)carbamate (2)

To a stirred solution of tert-butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (5 g, 14.2mmol) (from Example 3, Step 2) in DMF (50 mL) at 0° C., were added K₂CO₃(5.88 g, 42.61 mmol) and (Boc)₂O (4.89 mL, 21.31 mmol). The reactionmixture was warmed to RT and stirred for 16 h. The mixture was dilutedwith water (80 mL) and extracted with EtOAc (2×80 mL). The combinedorganic extracts were washed with brine (40 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified (silica gel; eluting with 15% EtOAc in hexanes) to affordcompound 2 (5 g, 78%) as pale yellow oil. ¹H NMR (500 MHz, DMSO-d₆): δ8.08 (s, 1H), 7.93-7.98 (m, 2H), 7.57 (br t, J=5.8 Hz, 1H), 7.46 (s,1H), 4.39 (br d, J=6.1 Hz, 2H), 1.55 (s, 9H), 1.42 (s, 9H).

Step 2: tert-Butyl((4-((tert-butoxycarbonyl)oxy)-6-(phenylethynyl)quinolin-2-yl)methyl)carbamate(3)

To a stirred solution of compound 2 (200 mg, 0.44 mmol) in TEA (5 mL) atRT under an inert atmosphere, was added CuI (84 mg, 0.44 mmol). Themixture was purged with argon for 10 min. To this was added Pd(PPh₃)₂Cl₂(31 mg, 0.04 mmol) and the mixture purged with argon for 10 min. Phenylacetylene (0.1 mL, 0.88 mmol) was added, and the mixture sealed and andheated to 100° C. for 18 h. The reaction mixture was cooled to RT, thendiluted with water (20 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with brine (15 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified (silica gel; eluting with 15% EtOAc in hexanes) to affordcompound 3 (70 mg, 33%) as orange oil.

¹H NMR (500 MHz, DMSO-d₆): δ 8.08 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.90(dd, J=8.7, 1.4 Hz, 1H), 7.55-7.64 (m, 3H), 7.43-7.47 (m, 3H), 4.40 (brd, J=5.8 Hz, 2H), 1.55 (s, 9H), 1.41 (s, 9H); LC-MS (ESI): m/z 475.2(M+H⁺).

Step 3: 2-(Aminomethyl)-6-(phenylethynyl)quinolin-4(1H)-onehydrochloride (Compound 1-7)

To a stirred solution of compound 3 (30 mg, 0.06 mmol) in DCM (1 mL) at0° C., was added 4 M HCl in 1,4-dioxane (1 mL, 4 mmol). The reactionmixture was gradually warmed to RT and stirred for 2 h. The mixture wasconcentrated under reduced pressure, and the residue was purified viatrituration with Et₂O (2×2 mL) and dried under vacuum to afford compound1-7 (14 mg, 74%) as pale brown solid. ¹H NMR (400 MHz, CD₃OD): δ 8.38(br s, 1H), 7.91 (br d, J=8.7 Hz, 1H), 7.73 (m, 1H), 7.53-7.59 (m, 2H),7.37-7.44 (m, 3H), 6.59 (br s, 1H), 4.31 (s, 2H); LC-MS (ESI): m/z 275.3(M+H⁺).

Example 8: Synthesis of2-(aminomethyl)-6-(1H-pyrazol-1-yl)quinolin-4(1H)-one hydrochloride(Compound 1-8)

Step 1: 1-(4-Nitrophenyl)-1H-pyrazole (2)

To a stirred solution of 1-fluoro-4-nitrobenzene 1 (2 g, 14.18 mmol) inDMF (20 mL) at 0° C. under an inert atmosphere, were added K₂CO₃ (5.87g, 42.55 mmol) and 1H-pyrazole (1.96 g, 28.37 mmol). The reactionmixture was sealed and heated at 120° C. for 8 h. The mixture was pouredinto ice-cold water (30 mL), and the obtained precipitated solid wascollected via filtration and dried under vacuum to afford compound 2(2.4 g) as yellow solid, which was not purified further.

Step 2: 4-(1H-Pyrazol-1-yl)aniline (3)

To a stirred solution of compound 2 (2.4 g, 12.7 mmol) in EtOH (20 mL)at RT, was added 10% Pd/C (50% wet, 500 mg). The reaction mixture wasstirred at RT under hydrogen (1 atmosphere pressure) for 16 h. Themixture was filtered through a pad of celite and the celite bed waswashed with methanol (30 mL). The filtrate was concentrated underreduced pressure to afford compound 3 (1.7 g, 79% over two steps) ascolorless oil, which did not require further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (d, J=2.0 Hz, 1H), 7.60 (d, J=1.4 Hz,1H), 7.42 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.42 (t, J=1.9 Hz,1H), 5.19 (s, 2H).

Step 3: Dimethyl 2-((4-(1H-pyrazol-1-yl)phenyl)amino)maleate (4)

To a stirred solution of compound 3 (1.4 g, 8.8 mmol) in EtOH (20 mL) at0° C., was added dimethyl acetylenedicarboxylate (1.62 mL, 13.21 mmol)drop-wise. The reaction mixture was warmed to RT and stirred for 2 h.The mixture was concentrated under reduced pressure. The residue waspurified (silica gel; eluting with 15-18% EtOAc in hexanes) to affordcompound 4 (2 g, 75%) as yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.65(s, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.70-7.77 (m, 3H), 7.06 (d, J=9.0 Hz,2H), 6.52 (m, 1H), 5.33 (s, 1H), 3.69 (s, 3H), 3.67 (s, 3H); LC-MS(ESI): m/z 301.9 (M+H⁺).

Step 4: Methyl4-oxo-6-(1H-pyrazol-1-yl)-1,4-dihydroquinoline-2-carboxylate (5)

To methanesulfonic acid (20 mL) was added phosphorus pentoxide (2 g) atRT and under an inert atmosphere, and the mixture was stirred for 1 h.Compound 4 (1.8 g, 5.98 mmol) was added, and the mixture was heated at50° C. for 1 h. The reaction mixture was poured into ice-cold water (50mL). The precipitated solid was collected via filtration and dried undervacuum to afford compound 5 (1.4 g, 87%) as pale yellow solid, which didnot require further purification.

¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.6 Hz,1H), 7.96 (m, 1H), 7.78 (br d, J=9.0 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H),6.60 (s, 1H), 6.53 (t, J=1.9 Hz, 1H), 3.84 (s, 3H); LC-MS (ESI): m/z269.9 (M+H⁺).

Step 5: 4-Oxo-6-(1H-pyrazol-1-yl)-1,4-dihydroquinoline-2-carboxamide (6)

To a stirred solution of compound 5 (500 mg, 1.86 mmol) in MeOH (10 mL)at RT, was added methanolic NH₃ (15 mL). The reaction mixture was sealedand heated at 80° C. for 6 h. The mixture was concentrated under reducedpressure to afford compound 6 (400 mg, 85%) as pale yellow solid, whichdid not require further purification ¹H NMR (400 MHz, DMSO-d₆): δ 8.44(d, J=2.3 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.97 (br s, 1H), 7.84 (dd,J=9.0, 2.7 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.11(br s, 1H), 6.59 (s, 1H), 6.51 (t, J=1.9 Hz, 1H); LC-MS (ESI): m/z 255.0(M+H⁺).

Step 6: tert-Butyl((4-((tert-butoxycarbonyl)oxy)-6-(1H-pyrazol-1-yl)quinolin-2-yl)methyl)carbamate(7)

To a stirred solution of compound 6 (400 mg, 1.57 mmol) in THF (15 mL)at 0° C. under an inert atmosphere, was added BH₃.DMS (5 M in ether,1.57 mL, 7.87 mmol) drop-wise. The reaction mixture was heated to refluxtemperature for 16 h. The mixture was poured into ice-cold water (20 mL)and basified with Na₂CO₃ (to pH ˜8). To this mixture at 0° C., wereadded THF (10 mL) and (Boc)₂O (0.54 mL, 2.36 mmol). The mixture waswarmed to RT and stirred for 16 h. The mixture was acidified with citricacid (to pH ˜5-6) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were washed with brine (20 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford compound 7(100 mg, 58%) as orange oil, which did not require further purification.¹H NMR (500 MHz, DMSO-d₆): δ 8.75 (d, J=2.3 Hz, 1H), 8.37 (dd, J=9.3,2.3 Hz, 1H), 8.29 (d, J=2.3 Hz, 1H), 8.14 (m, 1H), 7.85 (m, 1H), 7.58(m, 1H), 7.45 (s, 1H), 6.63 (m, 1H), 4.41 (br d, J=6.1 Hz, 2H), 1.57 (s,9H), 1.43 (s, 9H); LC-MS (ESI): m/z 441.1 (M+H⁺).

Step 7: 2-(Aminomethyl)-6-(1H-pyrazol-1-yl)quinolin-4(1H)-onehydrochloride (Compound 1-8)

To a stirred solution of compound 7 (100 mg, 0.23 mmol) in DCM (5 mL) at0° C., was added 4 M HCl in 1,4-dioxane (1 mL, 4 mmol). The mixture waswarmed to RT and stirred for 2 h. The solvent was decanted off, and theresidue was purified via trituration with Et₂O (2×3 mL) and dried undervacuum to afford compound 1-8 (60 mg, 95%) as pale yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.72 (br s, 3H), 8.65 (d, J=2.4 Hz, 1H), 8.46 (d,J=2.5 Hz, 1H), 8.29 (dd, J=9.0, 2.5 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H),7.80 (d, J=1.5 Hz, 1H), 6.59 (m, 1H), 6.53 (s, 1H), 4.20-4.23 (m, 2H);LC-MS (ESI): m/z 241.0 (M+H⁺).

Example 9: Synthesis of 2-(aminomethyl)-6-methoxyquinolin-4(1H)-onehydrochloride (Compound 1-9)

Step 1: tert-Butyl ((4-(benzyloxy)-6-bromoquinolin-2-yl)methyl)carbamate(2)

To a stirred solution of tert-butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (500 mg,1.42 mmol) (from Example 3, Step 2) in DMF (10 mL) at 0° C., were addedK₂CO₃ (588 mg, 4.26 mmol), benzyl bromide (0.2 mL, 1.7 mmol) followed byTBAI (cat.). The reaction mixture was warmed to RT and stirred for 16 h.The mixture was diluted with water (30 mL) and extracted with EtOAc(2×30 mL). The combined organic extracts were washed with brine (20 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified (silica gel; eluting with 20% EtOAc in hexanes) toafford compound 2 (500 mg, 79%) as white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.21 (s, 1H), 7.83-7.86 (m, 2H), 7.57 (d, J=7.0 Hz, 2H),7.38-7.49 (m, 4H), 7.12 (s, 1H), 5.36 (s, 2H), 4.33 (br d, J=5.9 Hz,2H), 1.42 (s, 9H); LC-MS (ESI): m/z 443.0 (M+H⁺).

Step 2: tert-Butyl((4-(benzyloxy)-6-hydroxyquinolin-2-yl)methyl)carbamate (3)

To a stirred solution of compound 2 (500 mg, 1.13 mmol) in a mixture of1,4-dioxane and water (1:1, 10 mL) at RT, was added KOH (248 mg, 4.51mmol). The mixture was purged with argon for 10 min. To this were added^(t)BuXphos (12 mg, 0.03 mmol) and Pd₂(dba)₃ (10 mg, 0.01 mmol), and themixture was purged with argon for another 10 min. The reaction mixturewas sealed and heated at 100° C. for 16 h. The mixture was diluted withwater (30 mL), acidified with citric acid (to pH ˜5-6) and extractedwith EtOAc (2×30 mL). The combined organic extracts were washed withbrine (20 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified (silica gel; eluting with 10% MeOH inDCM) to afford compound 3 (500 mg, impure) as pale yellow liquid. LC-MS(ESI): m/z 381.0 (M+H⁺). Compound 3 was obtained in a pure formfollowing the procedure outlined in Steps 3 and 4, below.

Step 3: tert-Butyl((4-(benzyloxy)-6-((tert-butoxycarbonyl)oxy)quinolin-2-yl)methyl)carbamate(4)

To a stirred solution of compound 3 (300 mg, 0.79 mmol) (from Step 2) inDMF (8 mL) at 0° C., were added K₂CO₃ (327 mg, 2.37 mmol) and (Boc)₂O(0.27 mL, 1.18 mmol). The mixture was warmed to RT and stirred for 16 h.The mixture was diluted with water (20 mL) and extracted with EtOAc(2×25 mL). The combined organic extracts were washed with brine (20 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified (silica gel; eluting with 20% EtOAc in hexanes) toafford compound 4 (120 mg, 32%) as pale yellow oil.

¹H NMR (500 MHz, CDCl₃): δ 7.97-8.02 (m, 2H), 7.38-7.56 (m, 7H), 6.81(s, 1H), 5.29 (s, 2H), 4.56 (br d, J=4.6 Hz, 2H), 1.56-1.60 (m, 18H);LC-MS (ESI): m/z 481.2 (M+H+).

Step 4: tert-Butyl((4-(benzyloxy)-6-hydroxyquinolin-2-yl)methyl)carbamate (3)

To a stirred solution of compound 4 (120 mg, 0.25 mmol) in MeOH (5 mL)at 0° C., was added K₂CO₃ (172 mg, 1.25 mmol). The reaction mixture waswarmed to RT and stirred for 2 h. The mixture was concentrated underreduced pressure. The residue was diluted with water (15 mL) andextracted with EtOAc (2×20 mL). The combined organic extracts werewashed with brine (15 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to afford pure compound 3 (80 mg, 84%) as paleyellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 9.95 (br s, 1H), 7.98 (br s, 1H), 7.78 (brd, J=8.4 Hz, 1H), 7.56 (br d, J=6.9 Hz, 2H), 7.35-7.49 (m, 4H), 7.28 (brd, J=7.8 Hz, 1H), 7.04 (br s, 1H), 5.33 (br s, 2H), 4.33 (br d, J=4.9Hz, 2H), 1.42 (s, 9H); LC-MS (ESI): m/z 381.1 (M+H⁺).

Step 5: tert-Butyl((4-(benzyloxy)-6-methoxyquinolin-2-yl)methyl)carbamate (5)

To a stirred solution of compound 3 (30 mg, 0.08 mmol) (from Step 4) inDMF (2 mL) at RT under an inert atmosphere, were added K₂CO₃ (33 mg,0.24 mmol) followed by iodomethane (0.01 mL, 0.24 mmol). The mixture wassealed and stirred at RT for 24 h. The mixture was diluted with water(10 mL) and extracted with EtOAc (2×10 mL). The combined organicextracts were washed with brine (10 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified (silicagel; eluting with 20% EtOAc in hexanes) to afford compound 5 (27 mg,87%) as pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 7.82 (d, J=9.3Hz, 1H), 7.56 (br d, J=7.2 Hz, 2H), 7.35-7.46 (m, 6H), 7.03 (s, 1H),5.37 (s, 2H), 4.30 (br d, J=5.8 Hz, 2H), 3.86 (s, 3H), 1.42 (s, 9H);LC-MS (ESI): m/z 395.1 (M+H⁺).

Step 6: (4-(Benzyloxy)-6-methoxyquinolin-2-yl)methanamine hydrochloride(6)

To a stirred solution of compound 5 (27 mg, 0.07 mmol) in THF (3 mL) at0° C., was added aq. 6 N HCl (3 mL). The reaction mixture was warmed toRT and stirred for 16 h. The mixture was concentrated under reducedpressure. The residue was purified via trituration with Et₂O (2×3 mL) toafford compound 6 (20 mg, 91%) as white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.42 (br s, 3H), 7.93 (d, J=9.0 Hz, 1H), 7.58 (br d, J=7.2Hz, 2H), 7.44-7.50 (m, 4H), 7.29-7.41 (m, 2H), 5.43 (s, 2H), 4.28-4.32(m, 2H), 3.89 (s, 3H); LC-MS (ESI): m/z 295.0 (M+H⁺).

Step 7: 2-(Aminomethyl)-6-methoxyquinolin-4(1H)-one hydrochloride(Compound 1-9)

To a stirred solution of compound 6 (20 mg, 0.06 mmol) in MeOH (5 mL) atRT, was added 10% Pd/C (50% wet, 5 mg). The reaction mixture was stirredat RT under hydrogen (1 atmosphere pressure) for 4 h. The mixture wasfiltered through a pad of celite and the celite bed was washed withmethanol (10 mL). The filtrate was concentrated under reduced pressureto afford compound 1-9 (14 mg, 96%) as pale yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.77 (br s, 3H), 7.84 (d, J=8.8 Hz, 1H), 7.47-7.54 (m,2H), 6.76 (s, 1H), 4.27 (s, 2H), 3.89 (s, 3H); LC-MS (ESI): m/z 204.9(M+H⁺).

Example 10: Synthesis of2-(aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinolin-4(1H)-onehydrochloride (Compound 1-47)

Step 1: tert-Butyl((6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate(2)

To a stirred solution of tert-butyl((6-bromo-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate 1 (50 mg, 0.16mmol) (from Example 3, Step 2) in MeCN (2 mL) at RT under an inertatmosphere, were added 1-methyl-1H-pyrazol-4-ylboronic acid (27 mg,0.208 mmol) and aq. 2M Na₂CO₃ (0.5 mL). The mixture was degassed underargon for 10 min. Pd(dppf)Cl₂ (10 mol %) was added and the mixture wasfurther degassed under argon for 10 min. The reaction mixture was sealedand heated at 100° C. for 70 min. The mixture was concentrated underreduced pressure. The residue was purified (silica gel; eluting with1-20% MeOH in DCM), to afford compound 2 (41 mg, 72%) as a solid. ¹H NMR(500 MHz, DMSO-d₆): δ 11.56 (s, 1H), 8.20 (s, 1H), 8.11 (m, 1H), 7.88(m, 1H), 7.82 (m, 1H), 7.50-7.55 (m, 2H), 5.89 (s, 1H), 4.10-4.15 (m,2H), 3.85 (s, 3H), 1.40 (s, 9H); LCMS Mass: 355.0 (M⁺+1).

Step 2: 2-(Aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinolin-4(1H)-onehydrochloride (Compound 1-47)

The title compound (1-47) (40 mg, 100%) was prepared from compound 2using the procedure described for Example 1, Step 3. ¹H NMR (500 MHz,DMSO-d₆): δ 8.81 (br s, 3H), 8.32 (s, 1H), 8.24 (m, 1H), 8.09 (m 1H),8.00 (s, 1H), 7.83 (m, 1H), 7.50 (br m, 1H), 6.77 (m, 1H), 4.23-4.33 (m,2H), 3.85 (s, 3H); LCMS Mass: 255.0 (M⁺+1).

Example 11: Synthesis of 2-(aminomethyl)-[6,8′-biquinolin]-4(1H)-onehydrochloride (Compound 1-65)

The title compound (1-65) was prepared using the procedure for Example10, using 8-quinolineboronic acid in Step 1. LCMS Mass: 302.0 (M⁺+1).

Example 12: Synthesis of2-(aminomethyl)-6-(5-(benzyloxy)pyridin-3-yl)quinolin-4(1H)-onehydrochloride (Compound 1-66)

The title compound (1-66) was prepared using the procedure for Example10, using3-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine inStep 1. LCMS Mass: 358.0 (M⁺+1).

Example 13: Synthesis of2-(aminomethyl)-6-(pyrimidin-5-yl)quinolin-4(1H)-one hydrochloride(Compound 1-40)

The title compound (1-40) was prepared using the procedure for Example10, using 5-pyrimidineboronic acid and DMF as solvent in Step 1. LCMSMass: 253.0 (M⁺+1).

Example 14: Synthesis of2-(aminomethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-onehydrochloride (Compound 1-74)

The title compound (1-74) was prepared using the procedure for Example10, using 2-(trifluoromethyl)pyridin-5-ylboronic acid in Step 1. LCMSMass: 320.0 (M⁺+1).

Example 15: Synthesis of2-(aminomethyl)-6-(4-fluorophenyl)quinolin-4(1H)-one hydrochloride(Compound 1-11)

The title compound (1-11) was prepared using the procedure for Example10, using (4-fluorophenyl)boronic acid in Step 1. LCMS Mass: 269.0(M⁺+1).

Example 16: Synthesis of2-(aminomethyl)-6-(2-chloro-4-fluorophenyl)quinolin-4(1H)-onehydrochloride (Compound 1-70)

The title compound (1-70) was prepared using the procedure for Example10, using (2-chloro-4-fluorophenyl)boronic acid in Step 1. LCMS Mass:303.0 (M⁺+1).

Example 17: Synthesis of2-(aminomethyl)-6-(3-fluoro-4-methoxyphenyl)quinolin-4(1H)-onehydrochloride (Compound 1-72)

The title compound (1-72) was prepared using the procedure for Example10, using (3-fluoro-4-methoxyphenyl)boronic acid in Step 1. LCMS Mass:299.0 (M⁺+1).

Example 18: Synthesis of 2-(aminomethyl)-6-phenoxyquinolin-4(1H)-onehydrochloride (Compound 1-21)

Step 1: tert-Butyl((4-(benzyloxy)-6-phenoxyquinolin-2-yl)methyl)carbamate (3)

To a stirred solution of tert-butyl((4-(benzyloxy)-6-hydroxyquinolin-2-yl)methyl)carbamate 1 (400 mg, 1.05mmol) (from Example 9, Step 4) in a mixture of DCM/DMF (8:2, 20 mL) atRT, were added 4 Å MS (400 mg), phenylboronic acid 2 (257 mg, 2.1 mmol),copper acetate (420 mg, 2.1 mmol) followed by pyridine (0.42 mL, 5.26mmol). The reaction mixture was stirred under oxygen atmosphere for 48h. The reaction mixture was filtered through a pad of celite. Thefiltrate was diluted with water (25 mL) and extracted with DCM (2×30mL). The combined organic extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudewas purified (silica gel; eluting with 15% EtOAc in hexanes) to affordcompound 3 (250 mg, 52%) as an off white semi-solid. ¹H NMR (500 MHz,CDCl₃): δ 7.98 (d, J=9.3 Hz, 1H), 7.78 (d, J=2.9 Hz, 1H), 7.36-7.47 (m,8H), 7.15 (t, J=7.4 Hz, 1H), 7.06 (d, J=7.8 Hz, 2H), 6.79 (s, 1H), 5.85(br s, 1H), 5.27 (s, 2H), 4.55 (br d, J=4.9 Hz, 2H), 1.51 (s, 9H); LCMSMass: 457.1 (M⁺+1).

Step 2: 2-(Aminomethyl)-6-phenoxyquinolin-4(1H)-one hydrochloride(Compound 1-21)

To a stirred solution of compound 3 (150 mg, 0.33 mmol) in a mixture ofMeOH (10 mL) and Conc. HCl (2 mL) at RT, was added 10% Pd/C (50% wet,100 mg). The reaction mixture was stirred at RT under hydrogen (1atmosphere pressure) for 16 h. The mixture was filtered through a pad ofcelite and the celite bed was washed with MeOH (10 mL). The filtrate wasconcentrated under reduced pressure, and the crude was purified viatrituration with Et₂O (2×6 mL) to afford compound 1-21 (90 mg, 91%) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.95 (br s, 1H), 8.68 (br s,3H), 7.80 (d, J=9.0 Hz, 1H), 7.55 (dd, J=9.0, 2.9 Hz, 1H), 7.42-7.48 (m,3H), 7.23 (m, 1H), 7.08-7.13 (m, 2H), 6.44 (br s, 1H), 4.17-4.20 (m,2H); LCMS Mass: 266.9 (M⁺+1).

Example 19: Synthesis of2-(aminomethyl)-6-(5-methyl-2-oxopyridin-1(2H)-yl)quinolin-4(1H)-onehydrochloride (Compound 1-46)

Step 1: tert-Butyl (4-(benzyloxy)-6-(5-methyl-2-oxopyridin-1(2H)-yl)quinolin-2-yl)methylcarbamate (2)

To a stirred solution of tert-butyl(4-(benzyloxy)-6-bromoquinolin-2-yl)methylcarbamate 1 (100 mg, 0.22mmol) (from Example 9, Step 1) in 1,4-dioxane (10 mL) at RT, were addedpotassium phosphate tribasic (180 mg, 0.68 mmol),5-methylpyridin-2(1H)-one (37 mg, 0.34 mmol), CuI (43 mg, 0.22 mmol)followed by N,N-dimethylethylenediamine (0.02 mL, 0.22 mmol). Thereaction mixture was purged with argon for 10 min. The mixture wassealed and stirred at 110° C. and for 16 h. The mixture was filteredthrough a pad of celite. The filtrate was diluted with water (20 mL) andextracted with EtOAc (2×20 mL). The combined organic extracts werewashed with brine (15 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude was purified (silica gel; eluting with3% MeOH in DCM) to afford compound 2 (70 mg, 66%) as pale yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 7.96-8.03 (m, 2H), 7.72 (dd, J=9.0, 2.3 Hz,1H), 7.54-7.57 (m, 3H), 7.36-7.48 (m, 5H), 7.15 (s, 1H), 6.45 (d, J=9.3Hz, 1H), 5.38 (s, 2H), 4.38 (br d, J=6.1 Hz, 2H), 2.06 (s, 3H), 1.43 (s,9H); LCMS Mass: 472.2 (M⁺+1).

Step 2: tert-Butyl(6-(5-methyl-2-oxopyridin-1(2H)-yl)-4-oxo-1,4-dihydroquinolin-2-yl)methylcarbamate(3)

To a stirred solution of compound 2 (70 mg, 0.15 mmol) in MeOH (5 mL) atRT, was added 10% Pd/C (50% wet, 20 mg). The reaction mixture wasstirred at RT under hydrogen (1 atmosphere pressure) for 4 h. Thereaction mixture was filtered through a pad of celite and the celite bedwas washed with methanol (10 mL). The filtrate was concentrated underreduced pressure to afford compound 3 (50 mg, 89%) as an off whitesolid, which did not require further purification.

¹H NMR (500 MHz, DMSO-d₆): δ 11.76 (br s, 1H), 7.93 (s, 1H), 7.62-7.69(m, 2H), 7.50-7.57 (m, 2H), 7.41 (dd, J=9.3, 2.3 Hz, 1H), 6.44 (d, J=9.5Hz, 1H), 5.97 (s, 1H), 4.17 (br d, J=5.8 Hz, 2H), 2.07 (s, 3H), 1.43 (s,9H); LCMS Mass: 382.1 (M+1).

Step 3: 2-(Aminomethyl)-6-(5-methyl-2-oxopyridin-1(2H)-yl)quinolin-4(1H)-one hydrochloride (Compound 1-46)

To a stirred solution of compound 3 (50 mg, 0.13) in DCM (2 mL) at 0°C., was added HCl in diethylether (1 mL). The reaction mixture wasgradually warmed to RT and stirred for 3 h. The mixture was concentratedunder reduced pressure. The crude was purified via trituration with Et₂O(2×3 mL), followed by MeCN (2×3 mL), then n-pentane (2×3 mL) to affordcompound 1-46 (25 mg, 60%) as pale yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 12.7 (br s, 1H), 8.65 (br s, 3H), 7.99 (s, 1H), 7.76 (s,2H), 7.54 (s, 1H), 7.42 (dd, J=9.5, 2.3 Hz, 1H), 6.46 (d, J=9.3 Hz, 1H),6.40 (br s, 1H), 4.17-4.20 (m, 2H), 2.08 (s, 3H); LCMS Mass: 280.2(M⁺−1).

Example 20: Synthesis of2-(aminomethyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-4(1H)-onehydrochloride (Compound 1-77)

The title compound (1-77) was prepared using the procedure for Example10, using (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid in Step 1.LCMS Mass: 321 (M⁺+1).

Example 21: Synthesis of2-(aminomethyl)-6-(2-methoxyethoxy)quinolin-4(1H)-one hydrochloride(Compound 1-78)

Step 1: tert-Butyl((4-(benzyloxy)-6-(2-methoxyethoxy)quinolin-2-yl)methyl)carbamate (2)

A mixture of tert-butyl((4-(benzyloxy)-6-hydroxyquinolin-2-yl)methyl)carbamate 1 (100 mg, 0.262mmol) (from Example 9, Step 4), K₂CO₃ (108 mg, 0.786 mmol),1-bromo-2-methoxyethane (100 μL, 1.05 mmol), DMF (1.5 mL), and DCM (1.0mL) was stirred at rt for 16 h. Additional 1-bromo-2-methoxyethane (100μL, 1.05 mmol) was added and the mixture heated at 75° C. for 5 h, thenheated at 50° C. for a further 16 h. The mixture was concentrated underreduced pressure and directly purified (silica gel; eluting with 45%EtOAc in hexanes) to afford compound 2 (59 mg, 51%) as an oil. LCMSMass: 439.0 (M⁺+1).

Step 2: (4-(Benzyloxy)-6-(2-methoxyethoxy)quinolin-2-yl)methanaminetrifluoroacetate (3)

To a stirred solution of compound 2 (59 mg, 0.134 mmol) in DCM (1.5 mL)at rt, was added 4M HCl in 1,4-dioxane (0.5 mL, 2.0 mmol). The mixturewas stirred at rt for 70 min. The mixture was concentrated under reducedpressure. The residue was purified via preparative reverse-phase HPLC(Waters XTerra® Prep MS C-18 OBD 5 μm 50×100 mm column; eluting with10-90% ACN/H₂O containing 0.1% TFA, over 20 min) to afford compound 3(60 mg, 100%) as an oil. LCMS Mass: 339.0 (M⁺+1).

Step 3: 2-(Aminomethyl)-6-(2-methoxyethoxy)quinolin-4(1H)-onehydrochloride (Compound 1-78)

The title compound (1-78) (27 mg, 75%) was prepared from compound 3using the procedure for Example 19, Step 2. ¹H NMR (300 MHz, DMSO-d₆): δ8.81 (br s, 3H), 7.92 (m, 1H), 7.45-7.58 (m, 2H), 6.91 (m, 1H),4.16-4.34 (m, 4H), 3.63-3.75 (m, 2H), 3.28 (s, 3H); LCMS Mass: 249.0(M⁺+1).

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-1000 mg of acompound described herein, or a pharmaceutically acceptable salt orsolvate thereof, is dissolved in sterile water and then mixed with 10 mLof 0.9% sterile saline. A suitable buffer is optionally added as well asoptional acid or base to adjust the pH. The mixture is incorporated intoa dosage unit form suitable for administration by injection

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound described herein, or a pharmaceutically acceptablesalt, or solvate thereof, is added to water (with optionalsolubilizer(s), optional buffer(s) and taste masking excipients) toprovide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound describedherein, or a pharmaceutically acceptable salt, or solvate thereof,20-50% by weight of microcrystalline cellulose, 1-10% by weight oflow-substituted hydroxypropyl cellulose, and 1-10% by weight ofmagnesium stearate or other appropriate excipients. Tablets are preparedby direct compression. The total weight of the compressed tablets ismaintained at 100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, is mixed with starch or other suitable powder blend.The mixture is incorporated into an oral dosage unit such as a hardgelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound described herein, or apharmaceutically acceptable salt, or solvate thereof, is placed intoSize 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and thecapsule is closed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compounddescribed herein, or a pharmaceutically acceptable salt, or solvatethereof, is mixed with hydroxypropyl celluose, propylene glycol,isopropyl myristate and purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

Example B-1: Human LOXL2 Amine Oxidase Activity Assay

LOXL2 amine oxidase activity is evaluated by measuring Amplex Redfluorescence using 10-20× concentrated conditioned media from CHO cellsstably expressing human LOXL2. To assay for amine oxidase activity, 10μL of the concentrated conditioned media is incubated with 2 μL of testcompound in DMSO and 73 μL Assay Buffer (50 mM Borate Buffer, pH8) for 2h at 37° C. After the 2 h incubation, 5 μl of 10 mM 1,5-Diaminopentane(DAP) diluted in Assay Buffer and 10 μl of Amplex Red Mix (8.5 μl AssayBuffer+0.5 μl of 10 mM Amplex Red+1 μl of 500 U/ml HorseradishPeroxidase) are added and the plate mixed and immediately placed on theFlexStaion for fluorescence measurements. Fluorescence is read inkinetic mode every 2 min for 1 hour at excitation=544 and emission=590.The amine oxidase activity is calculated from the slope of the linearportion of the curve.

TABLE 2 Compound Number IC₅₀ 1-1  A 1-2  C 1-3  A 1-4  A 1-5  A 1-6  A1-7  A 1-8  A 1-9  A 1-11 A 1-21 A 1-40 A 1-46 A 1-47 A 1-65 A 1-66 A1-70 A 1-72 A 1-74 A 1-77 A 1-78 A A is <0.3 μM; B is 0.3 to 1.0 μM; Cis >1.0 μM

Example B-2: LOXL2 Human Blood Amine Oxidase Activity Assay

The amine oxidase activity of human LOXL2 in the context of human wholeblood is measured using an Amplex Red assay. Since Human, recombinanthuman LOXL2 (purchased from Sino Biologicals, Beijing, China) is addedto human blood collected in heparin vacutainer tubes. Briefly, 0.5-2 μgrecombinant, human LOXL2 (reconstituted in water) and 2 μl test compoundin DMSO is added to 192 μl blood, mixed and incubated at 37° C. for 2 h.After the 2 h incubation, the blood is centrifuged at 2000×g for 15 minat room temperature to isolate the plasma. 50 μl of plasma is removedand mixed with 25 μl of 40 mM DAP (diluted in water) and 25 μl AmplexRed Mix (23.5 μl 50 mM Borate Buffer, pH8+0.5 μl 10 mM Amplex Red+1 μl500 U/ml Horseradish Peroxidase). Samples are mixed and immediatelyplaced on the FlexStaion for fluorescence measurements. Fluorescence isread in kinetic mode every 2 min for 1 hour at excitation=544 andemission=590. The amine oxidase activity is calculated from the slope ofthe linear portion of the curve.

Example B-3: Mouse Oropharyngeal Bleomycin Model of Lung Fibrosis

Lung fibrosis is induced in C57Bl/6 male mice by administering bleomycin(0.1-4 U/kg) via oropharyngeal instillation. Mice are either pretreatedwith vehicle or test compound (1 day to 1 hour) orally,intraperitoneally, intravenously or subcutaneously before bleomycininstallation (prophylactic dosing) or 7-14 days post bleomycininstillation (therapeutic dosing). The route and frequency of dosing arebased on previously determined pharmacokinetic properties for the LOXL2inhibitor in mouse. After bleomycin instillation animals are monitoreddaily for weight loss and clinical signs for 14-28 days prior tosacrifice. Animals are euthanized at study termination and weighed andblood (for isolation of plasma) and bronchoalveolar lavage are collectedand frozen for subsequent analyses. Lungs are removed, weighed, theneither inflated and fixed by instillation of 10% formalin and preparedfor histological examination or homogenized in 1 ml PBS for collagendetermination using a hydroxyproline assay. For histologicalexamination, lung slices are stained with Masson's trichrome orPicro-Sirius red to measure cross-linked collagen as an indicator offibrosis and an Ashcroft score of lung fibrotic and inflammatory damagedetermined. In addition, immunohistochemistry of fibrotic proteins suchas a-smooth muscle actin can be recorded. For lung hydroxyprolinecontent, 0.5 ml of the lung homogenate is removed and added to 0.5 ml 12N HCl and the samples heated at 120° C. overnight. After the acidhydrolysis, 25-100 μl of the supernatant is dried down, resuspended in25 μl water and the hydroxyproline content determined by the addition of0.5 ml Chloramine T solution (140 mg Chloramine T in 6.5 ml ddH₂0+1 mln-propanol+2.5 ml 1M sodium acetate) and incubation at room temperaturefor 20 min. After the incubation, 0.5 ml Erlich's solution (1.48 g of4-(dimethylamino(benzaldehyde) in 7 ml n-propanol+2.88 ml 60% perchloricacid and 0.12 ml ddH₂O) is added and incubated at 65° C. for 15 minbefore reading the absorbance at 550 nm. The concentration ofhydroxyproline in each skin biopsy is determined from a hydroxyproline(purchased from Sigma) standard curve.

Compound 1-3 (dosed prophylactically at 60 mg/kg p.o.) was efficaciousin this model.

Example B-4: Mouse Subcutaneous Bleomycin Model of Skin and Lun2Fibrosis

Skin and lung fibrosis is induced in female C57Bl/6 mice byadministering bleomycin via subcutaneous injection to two sites (50 μgbleo/site) on the backs of mice. Animals are anesthetized withisoflurane and bleomycin (100 μl, or PBS control) is injected at thesame site daily for 28 days to induce skin and lung fibrosis. Mice areeither pretreated with vehicle or test compound (1 day to 1 hour)orally, intraperitoneally, intravenously or subcutaneously beforebleomycin injection (prophylactic dosing) or 7-14 days post bleomycininjection (therapeutic dosing). Animals are euthanized at studytermination and weighed and blood (for isolation of plasma) andbronchoalveolar lavage are collected and frozen for subsequent analyses.Lungs are either removed, weighed, then homogenized in PBS fordetermination of collagen content using a hydroxyproline assay orinflated and fixed by instillation of 10% formalin and prepared forhistological examination by trichrome staining or Picrosirius redstaining. Skin biopsies are taken from each injection site using a 6 mmdermal punch biopsy (Acuderm). One punch biopsy is sandwiched in acassette with a sponge, placed in formalin and prepared for histologicalexamination by H&E staining, trichrome staining and/or Picrosirius redstaining. The other punch biopsy is placed in 0.5 ml PBS and mincedusing fine scissors. 500 μl 12 N HCl is then added and the samplesheated at 120° C. overnight. After the acid hydrolysis, 25-100 μl of thesupernatant is dried down, resuspended in 25 μl water and thehydroxyproline content determined by the addition of 0.5 ml Chloramine Tsolution (140 mg Chloramine T in 6.5 ml ddH₂0+1 ml n-propanol+2.5 ml 1Msodium acetate) and incubation at room temperature for 20 min. After theincubation, 0.5 ml Erlich's solution (1.48 g of4-(dimethylamino(benzaldehyde) in 7 ml n-propanol+2.88 ml 60% perchloricacid and 0.12 ml ddH₂0) is added and incubated at 65° C. for 15 minbefore reading the absorbance at 550 nm. The concentration ofhydroxyproline in each skin biopsy is determined from a hydroxyproline(purchased from Sigma) standard curve.

Example B-5: Rat/Mouse CCl₄ Model of Liver Fibrosis

Liver fibrosis is induced in mice (Balb/c or C57Bl/6) by intraperitonealadministration of CCl₄ (0.5-2 ml/kg body weight) diluted in corn oiltwice weekly for 4-8 weeks or by oral administration two-three timesweekly using an escalating dose protocol (Popov et al. 2011Gastroenterology; 140(5): 1642-1652.). Liver fibrosis is induced in ratsby either intraperitoneal administration (1-2.5 ml/kg) or by oraladministration in oil (mineral, olive or corn) twice weekly for 6-12weeks. LOXL2 inhibitors are delivered orally, intraperitoneally,intravenously or subcutaneously 1 day to 1 hour prior to the initialCCl₄ dosing (prophylactic dosing) or 1-4 weeks after the initial CCl₄dosing (therapeutic dosing). At the end of the study, mice aresacrificed by opening the chest cavity under isoflurane, blood is drawnvia cardiac puncture into EDTA vacutainer tubes and the liver isharvested. Part of the liver is fixed in 10% neutral buffered formalinfor subsequent histopathological analysis of inflammation and fibrosisby H&E staining and Picrosirius red staining. The remaining tissue issnap frozen at −80° C. for subsequent hydroxyproline analysis of totalcollagen content.

Example B-6: Mouse Mdr2 Knockout Model of Biliary Fibrosis

Liver disease develops in the BALB/cMdr2−/− mouse model with bridgingfibrosis/early cirrhosis between 8 and 12 weeks of age (Ikenaga et al.2015 Am J Pathology, 185: 325-334). LOXL2 inhibitors are deliveredorally, intraperitoneally, intravenously or subcutaneously intoBALB/c.Mdr2−/− mice once daily for 6 weeks beginning at week 6 afterbirth. At the end of the study, mice are anesthetized with isoflurane(1.5% v/v) via precise vaporizer. After laparotomy, portal pressure ismeasured directly by inserting a high-fidelity pressure catheter intothe portal vein and measuring pressure signals for 5 minutes. Serum iscollected for analysis of liver (ALT, AST, ALP, and bilirubin) andkidney (creatinine) biochemistries. Part of the liver is fixed in 10%neutral buffered formalin for histopathological analysis ofinflammation, necrosis and fibrosis by H&E staining and Picrosirius redstaining. Collagen content is determined from a portion of the livertissue using hydroxyproline analysis.

Example B-7: Mouse Alport Model of Kidney Fibrosis

Mice with mutations in one of the genes of glomerular basement membranecollagen, Collagen IV-a3/a4/a5, have defects in glomerular function withdevelopment of kidney fibrosis These mice develop renal dysfunction anddie prematurely of renal failure with specific timing dependent on thestrain background upon which the mutation is present. LOXL2 inhibitorsare administered orally to Col4A3 deficient mice on a SV129 backgroundeither prophylactically (ca. weeks 2-3 of age) or therapeutically (ca.weeks 4-6 wks of age). Mice are either sacrificed at a predefined time(7-9 wks of age) or continually dosed until they lose >15% of their bodyweight which preceeds death by 1-3 days. If specifically terminated,mice are perfused transcardially with PBS, and one kidney clamped at therenal artery and the other perfused with Dynabeads for magneticisolation of glomeruli. The other kidney is halved and a small sample ofrenal cortex fixed for transmission electron microscopic (TEM) analysisand a second sample of renal cortex used for RNA isolation. The otherhalf of the bisected kidney is embedded in OCT for immunohistochemicalanalysis. RNA from glomeruli and renal cortex is analyzed by real timeRT-PCR for genes of interest including MMP-10, MMP-12, IL6, MCP-1, TGF-b1, CTGF, MMP-2, and MMP-9. Immunohistochemical analysis will includestaining for collagen 1, CD45, fibronectin, smooth muscle actin, WT-1,and integrin alpha 8/laminin α5. Collagen 1 staining is blindly analyzedfor fibrosis scoring, and fibronectin staining is blindly analyzed forglomerulosclerosis scoring. For all studies albuminuria is assessedweekly and BUN at the time of tissue harvest.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound that has the structure of Formula (I),or a pharmaceutically acceptable salt, or solvate thereof:

wherein, each R¹ is independently H, D, or F; R² is Br, —CN, —OH,—OC₂-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,—S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴,—N(R⁵)₂, —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, —OC₁-C₆deuteroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆alkynyl; or R² isA-L¹-; L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—, C₁-C₆alkylene,—O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,—S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-; A is a cyclic ring thatis a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₃-C₁₀cycloalkenyl, or substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, wherein if A is substituted then A issubstituted with one or more R⁶; each R⁶ is independently H, D, halogen,CN, —OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,—C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,—C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, substitutedor unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₃-C₁₀deuterocycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁴ is independently asubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₃-C₁₀deuterocycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each R⁵ is independently H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₃-C₁₀deuterocycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two R⁵ groups attached tothe same N atom are taken together with carbon atom to which they areattached to form a substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; each R³ is independently H, D,halogen, —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl,—OC₁-C₆deuteroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, orC₁-C₆heteroalkyl; m is 0, 1, or
 2. 2. The compound of claim 1, or apharmaceutically acceptable salt, or solvate thereof, wherein: each R¹is H.
 3. The compound of claim 1 or claim 2, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein the compound has thestructure of Formula (II):


4. The compound of claim 1 or claim 2, or a pharmaceutically acceptablesalt, or solvate thereof, wherein the compound has the structure ofFormula (III):


5. The compound of claim 1 or claim 2, or a pharmaceutically acceptablesalt, or solvate thereof, wherein the compound has the structure ofFormula (IV):


6. The compound of any one of claims 1-5, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: R² is Br, —CN, —OH,—OC₂-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,—S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴,—N(R⁵)₂, —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₆alkenyl, orsubstituted or unsubstituted C₂-C₆alkynyl.
 7. The compound of any one ofclaims 1-6, or a pharmaceutically acceptable salt, or solvate thereof,wherein: R² is Br, substituted or unsubstituted C₂-C₆alkenyl, orsubstituted or unsubstituted C₂-C₆alkynyl.
 8. The compound of any one ofclaims 1-7, or a pharmaceutically acceptable salt, or solvate thereof,wherein: R² is Br.
 9. The compound of any one of claims 1-5, or apharmaceutically acceptable salt, or solvate thereof, wherein: R² isA-L¹-; L¹ is absent, —O—, —NR⁵—, C₁-C₄alkylene, —O(C₁-C₄alkylene)-, or—NR⁵(C₁-C₄alkylene)-; A is a cyclic ring that is a substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₃-C₈cycloalkenyl, or substituted or unsubstitutedC₂-C₈heterocycloalkyl, wherein if A is substituted then A is substitutedwith one or more R⁶.
 10. The compound of claim 9, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: L¹ is absent, —O—, —NH—,—OCH₂—, or —NHCH₂—.
 11. The compound of claim 9, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: L¹ is absent, or —O—. 12.The compound of any one of claims 1-5 or 9-11, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: A is a substituted orunsubstituted phenyl, wherein if A is substituted then A is substitutedwith one or more R⁶.
 13. The compound of any one of claims 1-5 or 9-11,or a pharmaceutically acceptable salt, or solvate thereof, wherein: A isa substituted or unsubstituted monocyclic heteroaryl, wherein if A issubstituted then A is substituted with one or more R⁶.
 14. The compoundof claim 13, or a pharmaceutically acceptable salt, or solvate thereof,wherein: A is a substituted or unsubstituted monocyclic 5-memberedheteroaryl or a substituted or unsubstituted monocyclic 6-memberedheteroaryl, wherein if A is substituted then A is substituted with oneor more R⁶.
 15. The compound of claim 13, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: A is substituted orunsubstituted monocyclic heteroaryl containing 1-4 N atoms and 0 or 1 Oor S atoms, or substituted or unsubstituted monocyclic heteroarylcontaining 0-4 N atoms and 1 O or S atoms, wherein if A is substitutedthen A is substituted with one or more R⁶.
 16. The compound of claim 13,or a pharmaceutically acceptable salt, or solvate thereof, wherein: A issubstituted or unsubstituted monocyclic heteroaryl that is a substitutedor unsubstituted furanyl, substituted or unsubstituted thienyl,substituted or unsubstituted pyrrolyl, substituted or unsubstitutedoxazolyl, substituted or unsubstituted thiazolyl, substituted orunsubstituted imidazolyl, substituted or unsubstituted pyrazolyl,substituted or unsubstituted triazolyl, substituted or unsubstitutedtetrazolyl, substituted or unsubstituted isoxazolyl, substituted orunsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl,substituted or unsubstituted thiadiazolyl, substituted or unsubstitutedpyridinyl, substituted or unsubstituted pyrimidinyl, substituted orunsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, or asubstituted or unsubstituted triazinyl, wherein if A is substituted thenA is substituted with one or more R⁶.
 17. The compound of any one ofclaims 1-5 or 9-11, or a pharmaceutically acceptable salt, or solvatethereof, wherein: A is substituted or unsubstituted C₃-C₆cycloalkyl,wherein if A is substituted then A is substituted with one or more R⁶.18. The compound of claim 17, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: A is substituted or unsubstitutedC₃-C₆cycloalkyl that is a substituted or unsubstituted cyclopropyl,substituted or unsubstituted cyclobutyl, substituted or unsubstitutedcyclopentyl, or substituted or unsubstituted cyclohexyl, wherein if A issubstituted then A is substituted with one or more R⁶.
 19. The compoundof claims 1-5 or 9-11, or a pharmaceutically acceptable salt, or solvatethereof, wherein: A is substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, wherein if A is substituted then A issubstituted with one or more R⁶.
 20. The compound of claim 19, or apharmaceutically acceptable salt, or solvate thereof, wherein: A issubstituted or unsubstituted C₂-C₁₀heterocycloalkyl that is substitutedor unsubstituted pyrrolidinonyl, substituted or unsubstitutedoxazolidinonyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,substituted or unsubstituted piperazinyl, substituted or unsubstitutedaziridinyl, substituted or unsubstituted azetidinyl, substituted orunsubstituted oxetanyl, substituted or unsubstituted thietanyl,substituted or unsubstituted homopiperidinyl, substituted orunsubstituted oxepanyl, substituted or unsubstituted thiepanyl,substituted or unsubstituted oxazepinyl, substituted or unsubstituteddiazepinyl, substituted or unsubstituted thiazepinyl, or substituted orunsubstituted 1,2,3,6-tetrahydropyridinyl, wherein if A is substitutedthen A is substituted with one or more R⁶.
 21. The compound of claim 1,or a pharmaceutically acceptable salt, or solvate thereof, wherein thecompound has the structure of Formula (Va), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein, L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—, C₁-C₆alkylene,—O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,—S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-; ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl; each R⁶ is independently H, D, halogen, CN,—OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,—OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,—NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁴ is independently asubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁵ is independently H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two R⁵ groups attached tothe same N atom are taken together with carbon atom to which they areattached to form a substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; each R³ is independently H, D,halogen, —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl; m is 0, 1, or2; n is 0, 1, 2, 3 or
 4. 22. The compound of claim 21, or apharmaceutically acceptable salt, or solvate thereof, wherein: L isabsent, —O—, —NH—, —OCH₂—, or —NHCH₂—.
 23. The compound of claim 21, ora pharmaceutically acceptable salt, or solvate thereof, wherein: L¹ isabsent, or —O—.
 24. The compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein the compound has thestructure of Formula (V), or a pharmaceutically acceptable salt, orsolvate thereof:

wherein, ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl; each R⁶ is independently H, D, halogen, CN,—OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,—OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,—NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁴ is independently asubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁵ is independently H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two R⁵ groups attached tothe same N atom are taken together with carbon atom to which they areattached to form a substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; each R³ is independently H, D,halogen, —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl; m is 0, 1, or2; n is 0, 1, 2 or
 3. 25. The compound of any one of claims 21-24, or apharmaceutically acceptable salt, or solvate thereof, wherein: ring

is a phenyl, monocyclic 6-membered heteroaryl, monocyclic 5-memberedheteroaryl, C₃-C₆cycloalkyl, or C₂-C₁₀heterocycloalkyl.
 26. The compoundof claim 25, or a pharmaceutically acceptable salt, or solvate thereof,wherein:


27. The compound of claim 25, or a pharmaceutically acceptable salt, orsolvate thereof, wherein:


28. The compound of claim 25, or a pharmaceutically acceptable salt, orsolvate thereof, wherein:

n is 0, 1, or
 2. 29. The compound of claim 28, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:


30. The compound of claim 25, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: ring

is C₃-C₆cycloalkyl that is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.
 31. The compound of claim 25, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: ring

is C₂-C₁₀heterocycloalkyl that is pyrrolidinonyl, oxazolidinonyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, or 1,2,3,6-tetrahydropyridinyl. 32.The compound of any one of claims 21-31, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: each R⁶ is independentlyH, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedmonocyclic C₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.
 33. The compound ofany one of claims 21-32, or a pharmaceutically acceptable salt, orsolvate thereof, wherein the compound has the structure of Formula (VIa)or Formula (VIIa):


34. The compound of any one of claims 21-32, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein the compound has thestructure of Formula (VIb) or Formula (VIIb):


35. The compound of claim 1, wherein the compound is:2-(Aminomethyl)-6-bromoquinolin-4(1H)-one;2-(Aminomethyl)-6-ethynylquinolin-4(1H)-one;2-(Aminomethyl)-6-phenylquinolin-4(1H)-one;2-(Aminomethyl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(phenylethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-pyrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-methoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-hydroxyquinolin-4(1H)-one;2-(Aminomethyl)-6-(4-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-1,2,3-triazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2H-tetrazol-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-tetrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-methyl-2H-tetrazol-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((2-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-phenoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(benzyloxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((2-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(phenylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(benzylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(prop-2-yn-1-yloxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(prop-2-yn-1-ylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrimidin-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrazin-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(oxazol-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(thiazol-2-yl)quinolin-4(1H)-one;2′-(Aminomethyl)-[2,6′-biquinolin]-4′(1′H)-one;2′-(Aminomethyl)-[3,6′-biquinolin]-4′(1′H)-one;2-(Aminomethyl)-6-(5-methyl-2-oxopyridin-1 (2H)-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1-phenyl-1H-pyrazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-phenyl-1H-pyrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-methyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-phenyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(3-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(4-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2′-(Aminomethyl)-3,4-dihydro-2H-[1,6′-biquinolin]-4′(1′H)-one;2-(Aminomethyl)-6-(4-phenylpiperazin-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3R,4R)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxamide;2-(Aminomethyl)-N-methyl-4-oxo-1,4-dihydroquinoline-6-carboxamide;2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxylic acid;2-(Aminomethyl)-6-isopropoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-isobutoxyquinolin-4(1H)-one;2-(Aminomethyl)-[6,8′-biquinolin]-4(1H)-one;2-(Aminomethyl)-6-(5-(benzyloxy)pyri din-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-chloro-4-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-chloro-2-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluoro-4-methoxyphenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluoro-4-methoxyphenyl)quinolin-4(1H)-one);2-(Aminomethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(5-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-methoxyethoxy)quinolin-4(1H)-one; or apharmaceutically acceptable salt, or solvate thereof.
 36. Apharmaceutical composition comprising a compound, or a pharmaceuticallyacceptable salt, or solvate thereof, of any one of claims 1-35 and atleast one pharmaceutically acceptable excipient.
 37. The pharmaceuticalcomposition of claim 36, wherein the pharmaceutical composition isformulated for administration to a mammal by intravenous administration,subcutaneous administration, oral administration, inhalation, nasaladministration, dermal administration, or ophthalmic administration. 38.The pharmaceutical composition of claim 36, wherein the pharmaceuticalcomposition is in the form of a tablet, a pill, a capsule, a liquid, asuspension, a gel, a dispersion, a solution, an emulsion, an ointment,or a lotion.
 39. A method of treating a disease or condition in a mammalthat would benefit from the inhibition or reduction of Lysyl oxidaselike-2 (LOXL2) activity comprising administering a substituted orunsubstituted 2-(aminomethyl)quinolin-4(1H)-one compound, orpharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof.
 40. The method of claim 39, wherein the disease orcondition is fibrosis or cancer.
 41. The method of claim 40, wherein thefibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis,cardiac fibrosis, peritoneal fibrosis, ocular fibrosis or cutaneousfibrosis.
 42. The method of claim 40, wherein the fibrosis ismyelofibrosis.
 43. The method of any one of claims 39-42, wherein thesubstituted or unsubstituted 2-(aminomethyl)quinolin-4(1H)-one compound,or pharmaceutically acceptable salt, or solvate thereof, has thestructure of Formula (I), or a pharmaceutically acceptable salt, orsolvate thereof:

wherein, each R¹ is independently H, D, or F; R² is H, D, F, Cl, Br, I,—CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,—S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴,—N(R⁵)₂, —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted —OC₁-C₆deuteroalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆alkynyl; or R² isA-L¹-; L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—, C₁-C₆alkylene,—O(C₁-C₆alkylene)-, —NR(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,—S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-; A is a cyclic ring thatis a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₃-C₁₀cycloalkenyl, or substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, wherein if R² is substituted then R² issubstituted with one or more R⁶; each R⁶ is independently H, D, halogen,CN, —OR, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴,—C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂,—C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, substitutedor unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁴ is independently asubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₃-C₁₀cyclodeuteroalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each R⁵ is independently H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₃-C₁₀cyclodeuteroalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two R⁵ groups attached tothe same N atom are taken together with carbon atom to which they areattached to form a substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; each R³ is independently H, D,halogen, —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl,—OC₁-C₆deuteroalkyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, orC₁-C₆heteroalkyl; m is 0, 1, or
 2. 44. The method of claim 43, wherein:each R¹ is H.
 45. The method of claim 43 or claim 44, wherein thecompound has the structure of Formula (II), Formula (III) or Formula(IV):

or a pharmaceutically acceptable salt, or solvate thereof.
 46. Themethod of any one of claims 43-45, wherein: R² is H, D, Br, —CN, —OH,—OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴,—S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴, —OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴,—N(R⁵)₂, —OC(═O)N(R⁵)₂, —C(═O)N(R⁵)₂, —NR⁵C(═O)R⁴, —NR⁵C(═O)OR⁴,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₆alkenyl, or substituted or unsubstitutedC₂-C₆alkynyl.
 47. The method of any one of claims 43-45, wherein: R² isH, F, Cl, Br, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₂-C₆alkenyl, or substituted or unsubstitutedC₂-C₆alkynyl.
 48. The method of any one of claims 43-47, wherein: R² isBr.
 49. The method of any one of claims 43-45, wherein: R² is A-L¹-; L¹is absent, —O—, —NR⁵—, C₁-C₄alkylene, —O(C₁-C₄alkylene)-, or—NR⁵(C₁-C₄alkylene)-; A is a cyclic ring that is a substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₃-C₈cycloalkenyl, or substituted or unsubstitutedC₂-C₈heterocycloalkyl, wherein if A is substituted then A is substitutedwith one or more R⁶.
 50. The method of claim 49, wherein: L¹ is absent,—O—, —NH—, —OCH₂—, or —NHCH₂—.
 51. The method of claim 49, wherein: L¹is absent, or —O—.
 52. The method of any one of claims 43-51, wherein: Ais a substituted or unsubstituted phenyl, wherein if A is substitutedthen A is substituted with one or more R⁶.
 53. The method of any one ofclaims 43-51, wherein: A is a substituted or unsubstituted monocyclicheteroaryl, wherein if A is substituted then A is substituted with oneor more R⁶.
 54. The method of claim 53, wherein: A is a substituted orunsubstituted monocyclic 5-membered heteroaryl or a substituted orunsubstituted monocyclic 6-membered heteroaryl, wherein if A issubstituted then A is substituted with one or more R⁶.
 55. The method ofclaim 53, wherein: A is substituted or unsubstituted monocyclicheteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, orsubstituted or unsubstituted monocyclic heteroaryl containing 0-4 Natoms and 1 O or S atoms, wherein if A is substituted then A issubstituted with one or more R⁶.
 56. The method of claim 53, wherein: Ais substituted or unsubstituted monocyclic heteroaryl that is asubstituted or unsubstituted furanyl, substituted or unsubstitutedthienyl, substituted or unsubstituted pyrrolyl, substituted orunsubstituted oxazolyl, substituted or unsubstituted thiazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedpyrazolyl, substituted or unsubstituted triazolyl, substituted orunsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl,substituted or unsubstituted isothiazolyl, substituted or unsubstitutedoxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted orunsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl,substituted or unsubstituted pyrazinyl, substituted or unsubstitutedpyridazinyl, or a substituted or unsubstituted triazinyl, wherein if Ais substituted then A is substituted with one or more R⁶.
 57. The methodof any one of claims 43-51, wherein: A is substituted or unsubstitutedC₃-C₆cycloalkyl that is a substituted or unsubstituted cyclopropyl,substituted or unsubstituted cyclobutyl, substituted or unsubstitutedcyclopentyl, or substituted or unsubstituted cyclohexyl, wherein if A issubstituted then A is substituted with one or more R⁶.
 58. The method ofclaims 43-51, wherein: A is substituted or unsubstitutedC₂-C₁₀heterocycloalkyl that is substituted or unsubstitutedpyrrolidinonyl, substituted or unsubstituted oxazolidinonyl, substitutedor unsubstituted piperidinyl, substituted or unsubstituted morpholinyl,substituted or unsubstituted thiomorpholinyl, substituted orunsubstituted piperazinyl, substituted or unsubstituted aziridinyl,substituted or unsubstituted azetidinyl, substituted or unsubstitutedoxetanyl, substituted or unsubstituted thietanyl, substituted orunsubstituted homopiperidinyl, substituted or unsubstituted oxepanyl,substituted or unsubstituted thiepanyl, substituted or unsubstitutedoxazepinyl, substituted or unsubstituted diazepinyl, substituted orunsubstituted thiazepinyl, or substituted or unsubstituted1,2,3,6-tetrahydropyridinyl, wherein if A is substituted then A issubstituted with one or more R⁶.
 59. The method of claim 43, wherein thecompound has the structure of Formula (Va), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein, L¹ is absent, —O—, —NR⁵—, —S—, —S═O—, —S(═O)₂—, C₁-C₆alkylene,—O(C₁-C₆alkylene)-, —NR⁵(C₁-C₆alkylene)-, —S(C₁-C₆alkylene)-,—S═O(C₁-C₆alkylene)-, or —S(═O)₂C₁-C₆alkylene-; ring

is an aryl, heteroaryl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, orC₂-C₁₀heterocycloalkyl; each R⁶ is independently H, D, halogen, CN,—OR⁵, —SR⁵, —S(═O)R⁴, —S(═O)₂R⁴, —S(═O)₂N(R⁵)₂, —NR⁵S(═O)₂R⁴, —C(═O)R⁴,—OC(═O)R⁴, —CO₂R⁵, —OCO₂R⁴, —N(R⁵)₂, —OC(═O)N(R⁵)₂, —NR⁵C(═O)R⁴,—NR⁵C(═O)OR⁴, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁴ is independently asubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,or substituted or unsubstituted heteroaryl; each R⁵ is independently H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆deuteroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two R⁵ groups attached tothe same N atom are taken together with carbon atom to which they areattached to form a substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; each R³ is independently H, D,halogen, —CN, —OH, —OC₁-C₆alkyl, —OC₁-C₆fluoroalkyl, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆deuteroalkyl, or C₁-C₆heteroalkyl; m is 0, 1, or2; n is 0, 1, 2, 3 or
 4. 60. The method of claim 59, wherein: L¹ isabsent, —O—, —NH—, —OCH₂—, or —NHCH₂—.
 61. The method of claim 59,wherein: L¹ is absent, or —O—.
 62. The method of claim 59, wherein: L¹is absent.
 63. The method of any one of claims 59-62, wherein:


64. The method of any one of claims 59-62, wherein:


65. The method of any one of claims 59-62, wherein:

n is 0, 1, or
 2. 66. The method of any one of claims 59-62, wherein:ring

is C₃-C₆cycloalkyl that is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.
 67. The method of any one of claims 59-62, wherein: ring

is C₂-C₁₀heterocycloalkyl that is pyrrolidinonyl, oxazolidinonyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, or 1,2,3,6-tetrahydropyridinyl. 68.The method of any one of claims 59-67, wherein: each R⁶ is independentlyH, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedmonocyclic C₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl.
 69. The method ofany one of claims 59-68, wherein the compound has the structure ofFormula (VIa) or Formula (VIIa):

or a pharmaceutically acceptable salt, or solvate thereof.
 70. Themethod of any one of claims 63-68, wherein the compound has thestructure of Formula (VIb) or Formula (VIIb):

or a pharmaceutically acceptable salt, or solvate thereof.
 71. Themethod of claim 39, wherein the compound is:2-(Aminomethyl)quinolin-4(1H)-one;2-(Aminomethyl)-1-methylquinolin-4(1H)-one;2-(Aminomethyl)-6-bromoquinolin-4(1H)-one;2-(Aminomethyl)-6-ethynylquinolin-4(1H)-one;2-(Aminomethyl)-6-phenylquinolin-4(1H)-one;2-(Aminomethyl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(phenylethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-pyrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-methoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-hydroxyquinolin-4(1H)-one;2-(Aminomethyl)-6-(4-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-1,2,3-triazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2H-tetrazol-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1H-tetrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-methyl-2H-tetrazol-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((2-fluorophenyl)ethynyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-phenoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-fluorophenoxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(benzyloxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((2-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4-fluorobenzyl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(phenylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(benzylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(prop-2-yn-1-yloxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)oxy)quinolin-4(1H)-one;2-(Aminomethyl)-6-(prop-2-yn-1-ylamino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((4,4,4-trifluorobut-2-yn-1-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3-phenylprop-2-yn-1-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyridin-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrimidin-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrazin-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(oxazol-2-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(thiazol-2-yl)quinolin-4(1H)-one;2′-(Aminomethyl)-[2,6′-biquinolin]-4′(1′H)-one;2′-(Aminomethyl)-[3,6′-biquinolin]-4′(1′H)-one;2-(Aminomethyl)-6-(5-methyl-2-oxopyridin-1(2H)-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1-methyl-1H-pyrazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(1-phenyl-1H-pyrazol-4-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-phenyl-1H-pyrazol-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-methyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-phenyl-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(3-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2-(Aminomethyl)-6-((1-(4-fluorophenyl)-1H-pyrazol-4-yl)amino)quinolin-4(1H)-one;2′-(Aminomethyl)-3,4-dihydro-2H-[1,6′-biquinolin]-4′(1′H)-one;2-(Aminomethyl)-6-(4-phenylpiperazin-1-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(pyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-((3R,4R)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl)quinolin-4(1H)-one;2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxamide;2-(Aminomethyl)-N-methyl-4-oxo-1,4-dihydroquinoline-6-carboxamide;2-(Aminomethyl)-4-oxo-1,4-dihydroquinoline-6-carboxylic acid;2-(Aminomethyl)-6-isopropoxyquinolin-4(1H)-one;2-(Aminomethyl)-6-isobutoxyquinolin-4(1H)-one;2-(Aminomethyl)-[6,8′-biquinolin]-4(1H)-one;2-(Aminomethyl)-6-(5-(benzyloxy)pyri din-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-chlorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-chloro-4-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-chloro-2-fluorophenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(3-fluoro-4-methoxyphenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-fluoro-4-methoxyphenyl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(5-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-4(1H)-one;2-(Aminomethyl)-6-(2-methoxyethoxy)quinolin-4(1H)-one; or apharmaceutically acceptable salt, or solvate thereof.
 72. The method ofany one of claims 39-71, wherein the compound is administered to themammal by intravenous administration, subcutaneous administration, oraladministration, inhalation, nasal administration, dermal administration,or ophthalmic administration.